Synthesis of both enantiomers of baclofen using (R)- and (S)-N-phenylpantolactam as chiral auxiliaries

Article abstract of DOI:10.1016/j.tetasy.2004.05.021

Esterification of racemic 4-nitro-3-(4-chlorophenyl)butanoic acid with (R)- or (S)-N-phenylpantolactam as the chiral auxiliary allowed us to obtain the (3R,3′R)- or (3S,3′S)-nitro esters with >98:2 dr after column chromatography. Hydrolysis of the resulti

Full text of DOI:10.1016/j.tetasy.2004.05.021

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 2039–2044
Synthesis of both enantiomers of baclofen using (R)- and
(S)-N-phenylpantolactam as chiral auxiliaries
*
*
~
Pelayo Camps, Diego Munoz-Torrero and Laura Sanchez
ꢀ
Laboratori de Quꢀımica Farmacꢁeutica, (Unitat Associada al CSIC), Facultat de Farmꢁacia, Universitat de Barcelona,
Av. Diagonal 643, E-08028 Barcelona, Spain
Received 3 May 2004; accepted 20 May 2004
Available online 24 June 2004
In memoriam of Dr. Juan Carlos del Amo
Abstract—Esterification of racemic 4-nitro-3-(4-chlorophenyl)butanoic acid with (R)- or (S)-N-phenylpantolactam as the chiral
auxiliary allowed us to obtain the (3R,30R)- or (3S,30S)-nitro esters with >98:2 dr after column chromatography. Hydrolysis of the
resulting diastereopure nitro esters gave the corresponding enantiopure nitro acids, which were readily converted in high yields into
either (R)- or (S)-baclofen hydrochloride.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Baclofen [c-amino-b-(4-chlorophenyl)butyric acid] 9, a
derivative of c-aminobutyric acid (GABA), modulates
the action of this central inhibitory neurotransmitter
and is used as an antispastic agent.1 Although baclofen
has been commercialized in its racemic form, its bio-
logical activity resides exclusively in the (À)-(R)-enan-
tiomer.2 Many syntheses of ( )-baclofen as well as its
enantiomers have already been described.3 Many of
these syntheses employ hydrolysis of b-(4-chlorophen-
yl)-c-butyrolactam as the last step. It is worthy of note
that a straightforward synthesis of ( )-baclofen by
reduction of the known ( )-4-nitro-3-(4-chlorophen-
yl)butanoic acid,4 ( )-4, has not yet been described.
Such a method could also be applied for the synthesis of
(þ)- and (À)-baclofen if a procedure to prepare both
enantiomers of the nitro acid 4 were developed. Herein
we report the first preparation of enantiopure nitro acids
(þ)- and (À)-4 by resolution of ( )-4 using (R)- and/or
(S)-N-phenylpantolactam 5, as chiral auxiliaries,5 and
their conversion into (À)- and (þ)-baclofen hydrochlo-
ride, respectively.
Nitro acid ( )-4 was prepared as shown in Scheme 1, by
a modification of the only described procedure.4 Methyl
4-chlorocinnamate, 2, prepared in 91% yield by reaction
of 4-chlorocinnamic acid, 1, with methanol and thionyl
chloride, was reacted with a 10-fold excess of nitro-
methane, using K2CO3/toluene and benzyltriethyl-
ammonium chloride for 24 h, instead of 1,1,3,3-
tetramethylguanidine/THF for 4 days, to give nitro ester
( )-3 in comparable yield (72% of distilled product).
Saponification of ( )-3 with 50% KOH/methanol gave
an impure product that required purification by silica gel
column chromatography, as reported.4 However, acidic
hydrolysis of ( )-3 (2 M HCl, AcOH, 1 h) gave pure
nitro acid ( )-4 in 85% yield, after selective solid–liquid
extraction using CH2Cl2 as the solvent, without the need
of column chromatography purification. Under these
conditions, a small amount of 2-(4-chlorophenyl)succi-
nic acid, formed through a Victor Meyer reaction,6 was
isolated. The amount of this by-product increased
when the reaction time or the HCl concentration was
increased.
Nitro acid ( )-4 was esterified with pantolactam (R)-5 to
give in good yield a 1:1 diastereomeric mixture of the
corresponding pantolactam esters (3R,30R)- and
(3S,30R)-7. Carefully conducted column chromatogra-
phy allowed the isolation of (3R,30R)-7 [>98:2 dr, by 1H
* Corresponding authors. Tel.: +34-93-402-45-36/42; fax: +34-93-403-
59-41; e-mail addresses: camps@ub.edu; dmunoztorrero@ub.edu
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.05.021

2040
P. Camps et al. / Tetrahedron: Asymmetry 15 (2004) 2039–2044
O2N
O2N
O
O
O
O
CH3NO2
K2CO3
2 M HCl
MeOH
SOCl2
OH
OMe
OMe
OH
AcOH
Cl
Cl
Cl
Cl
1
2
( )-3
( )-4
(R)-5 [or (S)-5]
OH
DCC, DMAP, CH2Cl2
DCC, DMAP, CH2Cl2
O
N
C6H5
(R)-5
[or (S)-5]
O
O
O
N
O2N
O2N
N
O
N
O
O
+
CH3NO2
O
O
O
CsF
Cl
Cl
Cl
(R)-6
(3R,3'R)-7 [or (3S,3'S)-7]
(3S,3'R)-7 [or (3R,3'S)-7]
dr >98:2, after column
chromatography
LiOH.H2O
THF/H2O
NiCl2, NaBH4
MeOH
Cl
H3N
O
O2N
NH
O
O
6 M HCl
1/ H2, Ra-Ni
2/ 2 M HCl
OH
OH
Cl
Cl
Cl
(R)-8
(−)-(R)-Baclofen
[or (+)-(S)-Baclofen]
(+)-(R)-4 [or (−)-(S)-4] >99% ee
+
(R)-5 [or (S)-5] >99% ee
Scheme 1.
NMR, 22.5% yield from ( )-4, 45% of the theoretical
1
with the ester of pantolactam ( )-5 and cinnamic acid,
under different reaction conditions [(a) CsF, toluene, or
CH2Cl2, benzyltriethylammonium chloride (BTEACl),
from À40 ꢁC till room temperature (rt);7 (b) K2CO3,
nitromethane as solvent and reagent, BTEACl, rt;8 (c)
KOH, EtOH, ultrasound irradiation, rt],9 gave mixtures
of the corresponding (3R*,30R*)- and (3S*,30R*)-dia-
yield] and diastereoenriched (3S,30R)-7 [92:8 dr, by H
NMR, 27.5% yield from ( )-4]. Hydrolysis of (3R,30R)-7
(>98:2 dr) with LiOHÆH2O in THF/H2O took place
efficiently to give (þ)-(R)-4 (84% yield, >99% ee by chi-
ral HPLC). It is noteworthy that in the above reaction,
pantolactam (R)-5 was recovered in enantiopure form
(91% yield), by simple liquid–liquid extraction taking
advantage of its neutral character. In a similar way,
hydrolysis of enantioenriched (3S,30R)-7 (92:8 dr) gave
(À)-(S)-4 (80% yield, 84% ee, by chiral HPLC). Unfor-
tunately, although the ee of this nitro acid could be in-
creased to 98% ee by repeated crystallization of its
cyclohexylamine salt from isopropanol, the yield of this
process was low.
1
stereomers in ratios from 1:1 to 1:1.7 (by H NMR).
Hydrogenation of enantiopure nitro acid (þ)-(R)-4 with
Ra-Ni in MeOH at 5 atm and room temperature gave,
after a basic work-up followed by treatment with
aqueous HCl, enantiopure (À)-(R)-baclofen hydrochlo-
ride, (À)-(R)-9ÆHCl, in 91% yield (Scheme 1), whose
NMR data and specific rotation were coincident with
the described values.10 Similarly, hydrogenation of nitro
acid (À)-(S)-4 gave (S)-baclofen hydrochloride, (þ)-(S)-
9ÆHCl.11
Consequently, to obtain enantiopure (S)-4, we repeated
the above resolution using (S)-5 as the chiral auxiliary.
In this way, (3S,30S)-7 [>98:2 dr, by 1H NMR, 21% yield
from ( )-4, 42% of the theoretical yield] and enantio-
Alternatively, (3R,30R)-7 was reduced with nickel
boride7 to give a mixture of lactam (À)-(R)-8, a known
precursor of (R)-baclofen,7 and the chiral auxiliary (R)-
5. Separation of this mixture could be performed by
silica gel column chromatography. Consequently, con-
version of (3R,30R)-7 into (R)-baclofen is more conve-
niently effected by hydrolysis followed by reduction of
the nitro group, which allows a more efficient and
practical recovery of the chiral auxiliary.
1
enriched (3R,30S)-7 [84:16 dr, by H NMR, 16.5% yield
from ( )-4] were obtained. Hydrolysis of (3S,30S)-7
(>98:2 dr) with LiOHÆH2O as before gave (S)-4 (91%
yield, >99% ee by chiral HPLC), with enantiopure (S)-5
being recovered in 91% yield.
A diastereomeric mixture of (3R,30R)- and (3S,30R)-7 in
the ratio of 1:1.4 was alternatively prepared by Michael
addition of nitromethane to ester (R)-6, derived from 4-
chlorocinnamic acid and (R)-N-phenylpantolactam, (R)-
5, using CsF as the base. As expected, a lower yield of the
first eluted (3R,30R)-7 (17% yield from nitro ester (R)-6,
96:4 dr) was obtained by column chromatography of the
above mixture. Similar Michael reactions carried out
3. Conclusion
(R)- and (S)-baclofen hydrochloride have been prepared
in enantiopure forms (>99% ee) from the readily avail-

P. Camps et al. / Tetrahedron: Asymmetry 15 (2004) 2039–2044
2041
able racemic nitro acid ( )-4, through a three-step syn-
thetic sequence, involving the resolution of the above
acid via diastereomeric esters derived from the chiral
auxiliaries (R)- and (S)-N-phenylpantolactam, (R)- and
(S)-5, followed by hydrolysis of the ester function and
hydrogenation (Ra-Ni) of the nitro group. The chiral
auxiliaries were efficiently recovered in enantiopure
forms after the hydrolysis step.
was added CH3NO2 (20.4 mL, 377 mmol) and the reac-
tion mixture stirred at room temperature for 24 h. Water
(300 mL) and Et2O (300 mL) were added, the organic
phase separated, dried over anhydrous Na2SO4 and
evaporated at reduced pressure. The crude product
(9.37 g) was distilled at 150–160 ꢁC/2.0Torr to give pure
( )-3 (7.10g, 72%) as a yellow oil.
4.3. ( )-4-Nitro-3-(4-chlorophenyl)butanoic acid ( )-4
4. Experimental
4.1. General
To a solution of nitro ester ( )-3 (0.25 g, 0.97 mmol)
in AcOH (2 mL) was added 2 M HCl (2 mL) and the
reaction mixture heated under reflux for 1 h. The solu-
tion was concentrated in vacuo, the residue taken up
in CH2Cl2 (10mL) and filtered. The filtrate was
evaporated at reduced pressure to yield nitro acid
( )-4 (0.20 g, 85%) as a white solid. Mp: 110–
111 ꢁC (CH2Cl2) [described 116–120 ꢁC (AcOEt/
CH2Cl2 4:1)].4 Chiral HPLC: (R)-4, tR ¼ 28:7 min,
k10 ¼ 5:15; (S)-4, tR ¼ 32:8 min, k20 ¼ 6:02; a ¼ 1:17;
Res. ¼ 2.90.
Melting points were determined in open capillary tubes
with an MFB 595010M Gallenkamp melting point
apparatus. 1H NMR (300 MHz) and 75.4 MHz 13C
NMR spectra were recorded on a Varian Gemini 300
spectrometer and 200 MHz 1H NMR spectra on a
Varian Gemini 200 equipment. Chemical shifts are given
in ppm (d scale) relative to internal TMS, while coupling
constants are reported in hertz (Hz). For the pantolac-
tam esters 6 and 7, the terms a or b are assigned to
hydrogen atoms or groups of the pantolactam moiety,
which are cis or trans relative to the carboxy substituent,
respectively. IR spectra were run on a FTIR Perkin–
Elmer model 1600 spectrophotometer. Absorption
values are expressed as wave-numbers (cmÀ1); only sig-
nificant absorption bands are given. HRMS were
performed on a Micromass Autospec spectrometer.
Column chromatography was performed on silica gel 60
AC.C. (70–200 mesh, SDS, ref 2100027). Thin-layer
chromatography (TLC) was performed with aluminum-
4.4. (3R,30R)- and (3S,30R)-4,4-Dimethyl-2-oxo-1-phen-
ylpyrrolidin-3-yl 4-nitro-3-(4-chlorophenyl)butanoate
(3R,30R)-7 and (3S,30R)-7
A mixture of nitro acid ( )-4 (2.40g, 9.87 mmol),
dicyclohexylcarbodiimide (DCC) (2.06 g, 9.98 mmol), 4-
(dimethylamino)pyridine (DMAP) (62.5 mg, 0.51
mmol), and (R)-5 (1.42 g, 6.92 mmol) in anhydrous
CH2Cl2 (56 mL) was stirred at room temperature for 1 h.
The precipitated DCU was filtered off and the filtrate
washed with 2 M HCl (3 · 100 mL) and saturated
aqueous NaHCO3 (3 · 100 mL), dried with anhydrous
Na2SO4 and evaporated at reduced pressure to give a
white oily residue (3.11 g), which was submitted to col-
umn chromatography [silica gel (300 g), hexane/Et2O
mixtures]. On elution with hexane/Et2O 45:55, (3R,30R)-
7 [702 mg, 22.5% yield from ( )-4, 45% of the theoretical
yield, >98:2 dr], and mixtures of (3R,30R)-7/(3S,30R)-7
[412 mg, 80:20 dr; 473 mg, 30:70 dr; 860 mg, 27.5% yield
from ( )-4, 8:92 dr] were successively isolated as color-
less oils.
backed sheets with silica gel 60F
(Merck, ref
254
1.05554), and the spots visualized with UV light and 1%
aqueous solution of KMnO4. Optical rotations were
measured on a Perkin–Elmer model 241 polarimeter.
Chiral HPLC analyses were performed on a Waters
model 600 liquid chromatograph provided with a
Waters model 486 variable k detector using a Chiralcel
OD-H column (25 · 0.46 cm) containing the chiral
stationary phase cellulose tris(3,5-dimethylphenyl-
carbamate), with a flow of 0.8 mL/min and UV detection
at k ¼ 254 nm. Conditions: mixture of hexane/isopro-
panol/AcOH in the ratio of 95:5:0.1 as eluent. Analytical
grade solvents were used for crystallization and chiral
HPLC analyses, while pure synthesis for solvents were
used in the reactions, extractions, and column chroma-
tography. NMR spectra were performed at the Serveis
20
D
(3R,30R)-7 (>98:2 dr): ½aꢀ ¼ þ40:1 (c 1.00, CH2Cl2). Rf
0.60 (SiO2, hexane/AcOEt 2:3). IR (NaCl) m: 1745 (C@O
st ester), 1710(C @O st lactam), 1553 (N@O st) cmÀ1. 1H
NMR (300 MHz, CDCl3) d 1.06 (s, 3H, 40a-CH3), 1.22
(s, 3H, 40b-CH3), 2.91 (dd, J ꢁ 16:2 Hz, J0 ꢁ 7:5 Hz, 1H)
and 2.99 (dd, J ¼ 16:2 Hz, J0 ¼ 6:9 Hz, 1H) (2-H2), 3.47
(d, J ¼ 9:6 Hz, 1H, 50a -H), 3.59 (d, J ¼ 9:6 Hz, 1H, 50b-
H), 4.02 (m, 1H, 3-H), 4.69 (dd, J ¼ 12:9 Hz,
J0 ¼ 8:1 Hz, 1H) and 4.87 (dd, J ꢁ 12:9 Hz, J0 ꢁ 6:5 Hz,
1H) (4-H2), 5.36 (s, 1H, 30-H), 7.14–7.40(complex sig-
nal, 7H, Ar-H C-phenyl and Ar-Hpara and Ar-Hmeta
N-phenyl), 7.56–7.60(m, 2H, H ortho N-phenyl). 13C
ꢀ
ꢁ
Cientıfico-Tecnics of the University of Barcelona, while
elemental analyses and high resolution mass spectra
were carried out at the Mycroanalysis Service of the
IIQAB (CSIC, Barcelona, Spain), and at the Mass
Spectrometry Laboratory of the University of Santiago
de Compostela (Spain), respectively.
4.2. ( )-Methyl 4-nitro-3-(4-chlorophenyl)butanoate
( )-34
NMR (75.4 MHz, CDCl3) d 21.0(CH , 40a-CH3), 24.6
3
(CH3, 40b-CH3), 37.3 (CH2þC, C2þC40), 39.4 (CH, C3),
57.6 (CH2,C50), 78.8 (CH, C30), 78.9 (CH2, C4), 119.4
(CH, Ar-Cortho N-phenyl), 125.0(CH, Ar-C para
N-phenyl), 128.7 (CH), 128.9 (CH) and 129.2 (CH)
To a À40 ꢁC mixture of 2 (7.50g, 38.1 mmol), K 2CO3
(10.5 g, 76.2 mmol), and benzyltriethylammonium chlo-
ride (0.87 g, 3.82 mmol) in anhydrous toluene (100 mL)

2042
P. Camps et al. / Tetrahedron: Asymmetry 15 (2004) 2039–2044
(Ar-Cmeta C-phenyl, Ar-Cmeta N-phenyl and Ar-Cor-
tho C-phenyl), 133.9 (C, Ar-Cpara C-phenyl), 136.6 (C,
Ar-Cipso C-phenyl), 138.7 (C, Ar-Cipso N-phenyl),
168.3 (C, C20), 169.5 (C, C1). Anal. Calcd for
C22H23ClN2O5: C, 61.33; H, 5.38; N, 6.50; Cl, 8.23.
Found: C, 61.39; H, 5.66; N, 6.42; Cl, 8.09.
6.50; Cl, 8.23. Found: C, 61.53; H, 5.52; N, 6.41; Cl,
8.36.
4.6. (R)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl 3-(4-
chlorophenyl)-2-propenoate (R)-6
20
D
(3S,30R)-7 (92:8 dr): ½aꢀ ¼ þ24:3 (c 1.04, CH2Cl2). Rf
A mixture of 4-chlorocinnamic acid 1 (681 mg,
0.60 (SiO2, hexane/AcOEt 2:3). IR (NaCl) m: 1744 (C@O
st ester), 1711 (C@O st lactam), 1553 (N@O st) cmÀ1. 1H
NMR (main diastereomer, 300 MHz, CDCl3) d 0.97 (s,
3H, 40a-CH3), 1.15 (s, 3H, 40b-CH3), 2.85 (dd,
J ¼ 15:9 Hz, J0 ¼ 8:1 Hz, 1H) and 2.96 (dd, J ¼ 15:9 Hz,
J0 ¼ 7:5 Hz, 1H) (2-H2), 3.46 (d, J ¼ 9:6 Hz, 1H, 50a-H),
3.58 (d, J ¼ 9:6 Hz, 1H, 50b-H), 4.04 (m, 1H, 3-H), 4.64
(dd, J ¼ 12:6 Hz, J0 ¼ 8:7 Hz, 1H) and 4.84 (dd,
J ¼ 12:6 Hz, J0 ¼ 6:3 Hz, 1H) (4-H2), 5.34 (s, 1H, 30-H),
7.15–7.40(complex signal, 7H, Ar-H C-phenyl and Ar-
Hpara and Ar-Hmeta N-phenyl), 7.56–7.60(m, 2H,
Hortho N-phenyl). 13C NMR (main diastereomer,
3.73 mmol), DCC (776 mg, 3.73 mmol), DMAP
(22.7 mg, 0.19 mmol) and (R)-5 (765 mg, 3.73 mmol) in
anhydrous CH2Cl2 (20mL) was stirred at room tem-
perature for 3 days. The precipitated DCU was filtered
off and the filtrate washed with 2 M HCl (3 · 40mL) and
saturated aqueous NaHCO3 (3 · 40mL), dried over
anhydrous Na2SO4 and evaporated at reduced
pressure to give a brown oily residue (1.09 g), which was
submitted to column chromatography [silica gel (75 g);
hexane/Et2O mixtures]. On elution with hexane/Et2O
65:35, pure ester (R)-6 was obtained as a white solid
(701 mg, 51% yield). Mp: 130–131 ꢁC (hexane/Et2O
20
75.4 MHz, CDCl3) d 21.0(CH , 40a-CH3), 24.6 (CH3,
65:35). Rf 0.38 (SiO2, hexane/Et2O 1:1). ½aꢀ ¼ À46:1
3
D
40b-CH3), 37.3 (C, C40), 37.7 (CH2, C2), 40.0 (CH, C3),
(c 1.04, CHCl3). IR (KBr) m: 1730(C @O st ester),
57.7 (CH2, C50), 78.8 (CH, C30), 79.0(CH , C4), 119.5
1701 (C@O st lactam) cmÀ1 1H NMR (300 MHz,
.
2
(CH, Ar-Cortho N-phenyl), 125.1 (CH, Ar-Cpara N-
phenyl), 128.8 (CH), 129.0(CH), and 129.2 (CH) (Ar-
Cmeta C-phenyl, Ar-Cmeta N-phenyl and Ar-Cortho C-
phenyl), 134.0(C, Ar-C para C-phenyl), 136.5 (C, Ar-
Cipso C-phenyl), 138.8 (C, Ar-Cipso N-phenyl), 168.3
(C, C20), 169.8 (C, C1). Anal. Calcd for C22H23ClN2O5:
C, 61.33; H, 5.38; N, 6.50; Cl, 8.23. Found: C, 61.55; H,
5.61; N, 6.51; Cl, 8.27.
CDCl3) d 1.19 (s, 3H, 40a-CH3), 1.35 (s, 3H, 40b-CH3),
3.55 (d, J ¼ 9:5 Hz, 1H, 50a-H), 3.66 (d, J ¼ 9:5 Hz, 1H,
50b-H), 5.54 (s, 1H, 30-H), 6.55 (d, J ¼ 16:1 Hz, 1H,
2-H), 7.18 (tt, J ¼ 7:4 Hz, J0 ¼ 1:2 Hz, 1H, Ar-Hpara
N-phenyl), 7.35–7.51 (complex signal, 6H, Ar-H
C-phenyl and Ar-Hmeta N-phenyl), 7.62–7.66 (m, 2H,
Hortho N-phenyl), 7.75 (d, J ¼ 16:1 Hz, 1H, 3-H). 13C
NMR (75.4 MHz, CDCl3) d 21.3 (CH3, 40a-CH3), 25.0
(CH3, 40b-CH3), 37.6 (C, C40), 57.8 (CH2, C50), 78.4
(CH, C30), 117.6 (CH, C2), 119.4 (CH, Ar-Cortho N-
phenyl), 124.9 (CH, Ar-Cpara N-phenyl), 128.9 (CH),
129.1 (CH) and 129.3 (CH) (Ar- Cmeta C-phenyl, Ar-
Cmeta N-phenyl and Ar-Cortho C-phenyl), 132.7 (C,
Ar-Cpara C-phenyl), 136.4 (C, Ar-Cipso C-phenyl),
139.0(C, Ar-C ipso N-phenyl), 144.6 (CH, C3), 165.8 (C,
C20), 168.9 (C, C1). Anal. Calcd for C21H20ClNO3: C,
68.20; H, 5.45; N, 3.79; Cl, 9.59. Found: C, 68.41; H,
5.58; N, 3.80; Cl, 9.75.
4.5. (3S,30S)- and (3R,30S)-4,4-Dimethyl-2-oxo-1-phenyl-
pyrrolidin-3-yl 4-nitro-3-(4-chlorophenyl)butanoate
(3S,30S)-7 and (3R,30S)-7
These were prepared in a similar manner to that des-
cribed for (3R,30R)-7 and (3S,30R)-7. From nitro acid
( )-4 (3.50g, 14.4 mmol), DCC (3.00g, 14.5 mmol),
DMAP (91 mg, 0.74 mmol), (S)-5 (2.07 g, 10.1 mmol)
and anhydrous CH2Cl2 (82 mL), a diastereomeric mix-
ture of (S)-pantolactam esters (4.33 g) was obtained. An
aliquot part of this crude product (3.84 g) was submitted
to column chromatography [silica gel (300 g), hexane/
Et2O mixtures]. On elution with hexane/Et2O 45:55, (3S,
30S)-7 [805 mg, 21% from ( )-4, 42% of the theoretical
yield, >98:2 dr], and mixtures of (3S,30S)-7/(3R,30S)-7
[740mg, 80:20dr; 680mg, 33:67 dr; 642 mg, 16.5% yield
from ( )-4, 16:84 dr] were successively isolated as col-
orless oils.
4.7. (3R,30R)-7 and (3S,30R)-7 from the Michael addition
of nitromethane to (R)-6
To a À40 ꢁC solution of (R)-6 (500 mg, 1.35 mmol),
CsF (2.05 g, 13.5 mmol), benzyltriethylammonium
chloride (30.7 mg, 0.13 mmol) in anhydrous toluene
(3.25 mL) was added CH3NO2 (0.73 mL, 13.5 mmol)
and the reaction mixture stirred at room temperature
for 4 h. Water (20mL) and Et 2O (20mL) were added,
the organic phase was separated, dried over anhy-
drous Na2SO4 and evaporated at reduced pressure to
give a brown oily residue consisting of a mixture of
(3R,30R)-7 and (3S,30R)-7 (516 mg, dr 1:1.4), which
was submitted to column chromatography [silica gel
(52 g), hexane/Et2O mixtures]. On elution with hexane/
Et2O 55:45, (3R,30R)-7 (99 mg, 17% yield from the
nitro ester (R)-6, 96:4 dr) and mixtures of
(3R,30R)-7/(3S,30R)-7 [85 mg, 56:44 dr; 94 mg, 10:90 dr;
51 mg, 9:91 dr] were successively eluted as light white
oils.
20
(3S,30S)-7 (>98:2 dr): ½aꢀ ¼ À41:0 (c 1.80, CH2Cl2).
D
1
The IR, H and 13C NMR spectra are coincidental with
those of (3R,30R)-7. Anal. Calcd for C22H23ClN2O5: C,
61.33; H, 5.38; N, 6.50; Cl, 8.23. Found: C, 61.22; H,
5.58; N, 6.35; Cl, 8.36.
20
(3R,30S)-7 (84:16 dr): ½aꢀ ¼ À26:4 (c 0.98, CH2Cl2).
D
1
The IR spectra and the H and 13C NMR signals of the
main diastereomer are coincidental with those of the
main diastereomer of (3S,30R)-7/(3R,30R)-7 (92:8 dr).
Anal. Calcd for C22H23ClN2O5: C, 61.33; H, 5.38; N,

P. Camps et al. / Tetrahedron: Asymmetry 15 (2004) 2039–2044
2043
20
D
28
D
4.8. (R)-4-Nitro-3-(4-chlorophenyl)butanoic acid (R)-4
½aꢀ ¼ À38 (c 1.02, EtOH), lit. ½aꢀ ¼ À39 (c 1.0,
EtOH).12 Mp: 105–107 ꢁC (EtOH) [lit. 112 ꢁC (CH2Cl2/
To a 0 ꢁC solution of ester (3R,30R)-7 (650mg,
1.51 mmol, >98:2 dr) in THF/H2O 2:1 (9 mL) was
added LiOHÆH2O (69 mg, 1.66 mmol) and the reaction
mixture was stirred at room temperature for 4 h. More
LiOHÆH2O (25 mg, 0.60 mmol) was added and stirring
at room temperature continued for 16 h. Finally,
more LiOHÆH2O (31 mg, 0.75 mmol) was added and
the mixture stirred at room temperature for 5 h. The
organic solvent was removed at reduced pressure, the
aqueous phase extracted with CH2Cl2 (3 · 15 mL),
and the combined organic extracts dried with anhydrous
Na2SO4 and evaporated at reduced pressure, recovering
pantolactam (R)-5 (282 mg, 91% yield, >99% ee by
chiral HPLC). The aqueous phase was acidified
with 2 M HCl (2 mL) and extracted with AcOEt
(3 · 15 mL). The combined organic extracts were dried
over anhydrous Na2SO4 and evaporated at reduced
pressure to yield nitro acid (R)-4 (309 mg, 84% yield,
MeOH 95:5)].12
4.11. (R)-4-Amino-3-(4-chlorophenyl)butanoic acid
hydrochloride, [(R)-baclofen hydrochloride] (R)-9ÆHCl
A mixture of (R)-4 (88 mg, 0.36 mmol), MeOH (15 mL)
and Ra-Ni (50% water content, 200 mg) was hydroge-
nated at 5 atm at room temperature for 24 h. The
reaction mixture was made basic with 0.1 M NaOH
(3.6 mL, 0.36 mmol) and the catalyst filtered off in vacuo
through Celiteꢂ. The filtrate was evaporated under re-
duced pressure, the residue taken up in 2 M HCl
(0.5 mL), and the resulting aqueous phase washed with
AcOEt (2 · 10mL) and evaporated at reduced pressure.
The resulting solid was taken up in MeOH (3 mL) and
filtered. The filtrate was evaporated at reduced
pressure to give (R)-9ÆHCl (83 mg, 91% yield) as a white
20
28
>99% ee by chiral HPLC) as a light yellow solid.
solid. ½aꢀ ¼ À2:0 (c 0.60, H2O), lit. ½aꢀ ¼ À2 (c 0.6,
D
D
20
D
½aꢀ ¼ þ10:5 (c 2.04, MeOH). Chiral HPLC: (R)-4,
H2O).10 Mp: 194–195 ꢁC (MeOH) [lit. 195 ꢁC (isopro-
1
tR ¼ 28:7 min. Mp: 79–81 ꢁC (AcOEt). Rf 0.17 (SiO2,
hexane/Et2O 1:1). IR (KBr) m: 3500–2500 (O–H st),
panol)].10 Rf 0.12 (SiO2, hexane/Et2O 1:1). The IR, H
NMR and 13C NMR data are coincidental with those
described.10
1
1699 (C@O st), 1557 (N@O st) cmÀ1. The H and 13C
NMR spectra are coincidental with those of ( )-4.
HRMS calcd for C10H10ClNO4: 243.0298. Found:
243.0296.
4.12. (S)-4-Amino-3-(4-chlorophenyl)butanoic acid
hydrochloride, [(S)-baclofen hydrochloride] (S)-9ÆHCl
4.9. (S)-4-Nitro-3-(4-chlorophenyl)butanoic acid (S)-4
It was prepared in a similar manner to that described for
(R)-9ÆHCl. From the nitro acid (S)-4 (101 mg,
0.41 mmol), MeOH (15 mL) and Ra-Ni (50% water
This was prepared in a similar manner to that described
for (R)-4. From (3S,30S)-7 (588 mg, 1.37 mmol, >98:2
content, 200 mg), amino acid (S)-9ÆHCl (94 mg, 91%
20
D
dr),
LiOHÆH2O
(63 mg,
1.50mmol þ23 mg,
yield) was obtained as a white solid. ½aꢀ ¼ þ2:0 (c 0.60,
28
D
0.54 mmolþ28 mg, 0.68 mmol), pantolactam (S)-5
H2O) [lit. ½aꢀ ¼ þ1:4 (c 1.0, H2O)].11 Mp: 194–195 ꢁC
(254 mg, 91% yield, >99% ee by chiral HPLC) and nitro
acid (S)-4 (309 mg, 93% yield, >99% ee by chiral HPLC)
(MeOH) [lit. 215 ꢁC (EtOH/Et2O)].13 The Rf , IR, 1H
NMR and 13C NMR spectra are coincidental with those
of (R)-9ÆHCl.
20
D
were separately obtained. ½aꢀ ¼ À10:1 (c 2.00, MeOH).
Chiral HPLC: (S)-4, tR ¼ 32:8 min. Mp: 78–79 ꢁC
(AcOEt). Rf 0.17 (SiO2, hexane/Et2O 1:1). IR (KBr) m:
3500–2500 (O–H st), 1698 (C@O st), 1556 (N@O
st) cmÀ1. The 1H and 13C NMR spectra are coincidental
with those of ( )-4. HRMS calcd for C10H10ClNO4:
243.0298. Found: 243.0295.
Acknowledgements
A fellowship from the Generalitat de Catalunya to
ꢀ
L. Sanchez and financial support from the Direccion
General de Investigacion of Ministerio de Ciencia y
ꢀ
ꢀ
4.10. (R)-4-(4-Chlorophenyl)pyrrolidin-2-one (R)-8
ꢀ
Tecnologıa and FEDER (project PPQ2002-01080) and
Comissionat per a Universitats i Recerca of the Genera-
litat de Catalunya (project 2001-SGR-00085) are
gratefully acknowledged. We thank the Serveis
To a stirred solution of (3R,30R)-7 (485 mg, 1.13 mmol,
>98:2 dr) in MeOH (8 mL) was added NiCl2Æ6H2O
(536 mg, 2.25 mmol) at room temperature. After stirring
for 5 min, NaBH4 (461 mg, 12.1 mmol) was added in
four portions. The reaction mixture was stirred for
30min at room temperature and filtered in vacuo
through Celiteꢂ. The solid material was thoroughly
washed with MeOH. The combined filtrate and wash-
ings were evaporated under reduced pressure to obtain a
residue (1.05 g), that was submitted to column chroma-
tography [silica gel (25 g), Et2O/AcOEt mixtures]. On
elution with Et2O, (R)-5 (200 mg, 98% yield, >99% ee)
was recovered; on elution with Et2O/AcOEt 50:50, (R)-8
(97 mg, 44% yield) was obtained as a white solid.
ꢀ
Cientıfico-Tecnics of the University of Barcelona for
NMR facilities and Ms. P. Domenech from the IIQAB
ꢁ
ꢁ
(CSIC, Barcelona, Spain) for carrying out the elemental
analyses.
References and notes
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C. G. J. Med. Chem. 1991, 4, 1307–1313.

2044
P. Camps et al. / Tetrahedron: Asymmetry 15 (2004) 2039–2044
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~
ꢀ
^
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