A short and convenient chemoenzymatic synthesis of both enantiomers of 3-phenylGABA and 3-(4-chlorophenyl)GABA(Baclofen)

Article abstract of DOI:10.1016/j.tetasy.2005.02.019

Both enantiomers of the pharmacologically active GABA analogues 4-amino-3-phenyl and 4-amino-3-(4-chlorophenyl)butyric acid (Baclofen) with high enantiomeric excesses were synthesized by a chemoenzymatic method involving α-chymotrypsin mediated kinetic resolutions of the corresponding 3-phenyl- and 3-(4-chlorophenyl)-4-nitrobutyric acid methyl ester precursors.

Full text of DOI:10.1016/j.tetasy.2005.02.019

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1341–1345
A short and convenient chemoenzymatic synthesis
of both enantiomers of 3-phenylGABA and
3-(4-chlorophenyl)GABA (Baclofen)
Fulvia Felluga,* Valentina Gombac, Giuliana Pitacco and Ennio Valentin*
`
Dipartimento di Scienze Chimiche, Universita di Trieste, via Licio Giorgieri 1, I-34127 Trieste, Italy
Received 20 December 2004; accepted 18 February 2005
Abstract—Both enantiomers of the pharmacologically active GABA analogues 4-amino-3-phenyl and 4-amino-3-(4-chlorophen-
yl)butyric acid (Baclofen) with high enantiomeric excesses were synthesized by a chemoenzymatic method involving a-chymotrypsin
mediated kinetic resolutions of the corresponding 3-phenyl- and 3-(4-chlorophenyl)-4-nitrobutyric acid methyl ester precursors.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
agonist known. Although still commercialized in its
racemic form, (Lioresalꢁ and Baclonꢁ), the biological
activity of Baclofen, as well as that of b-phenylGABA,
is known to reside in the (R)-enantiomer,5,6 with the
(S)-antipode showing a lower affinity to the same recep-
tor site. Due to the increasing demand of enantiomeri-
cally pure drugs from the pharmaceutic industry, the
enantioselective synthesis of compounds such as 3 and
4 in their enantiomerically pure, active form is an impor-
tant target.
GABA (c-aminobutyric acid), is a major inhibitory neu-
rotransmitter in the mammalian Central Nervous Sys-
tem (CNS),1 and decreased GABAÕergic activity results
in the excessive excitement of CNS (namely Neuronal
Firing).2 The disfunctioning of the central GABA sys-
tem is responsible for the development and outbreak
of epilepsy, HuntingtonÕs and ParkinsonÕs diseases,3
and other psychiatric disorders, such as anxiety and
pain.
Some examples of optical resolution via diastereomeric
compounds,6,9 a number of stereoselective syntheses of
the enantiomers of Baclofen have been reported in the
The direct administration of GABA is not an efficient
therapy because due to its hydrophilic nature, it very
poorly crosses the blood–brain barrier.4 b-Aryl-c-ami-
nobutyric acids, particularly 4-amino-3-phenylbutyric
acid5 (b-phenylGABA) and 4-amino-3-(4-chlorophen-
yl)butyric acid (Baclofen)6 are lipophilic analogues of
GABA. Although very closely related in structure, b-
phenylGABA and Baclofen show different pharmaco-
logical activities. The former is in fact a mood elevator
and tranquillizer,7 while Baclofen is widely used as a
muscle relaxant in the treatment of spasticy8 caused by
diseases at the spinal cord, in particular following trau-
matic lesions or associated with multiple sclerosis.
literature,10 some of which involve an enzymatic step.11
10e,12
Examples of enantioselective
and chemoenzymatic
syntheses13 of (R)-(ꢀ)- and (S)-(+)-b-phenylGABA has
also been published.
Herein we report a very short and convenient synthesis
of both enantiomers of b-phenylGABA and Baclofen,
obtained in excellent enantiomeric excess and good yield
by a few step procedure, involving the use of a-chymo-
trypsin in the enantiodifferentiating step.
Baclofen was first synthesized in 1962, and it is the most
selective and the only therapeutically available GABAB
2. Results and discussion
The Michael addition of nitromethane to methyl cynna-
mate 1 and methyl p-chlorocynnamate 2, respectively,
catalyzed by 1,1,3,3-tetramethylguanidine,14 proceeded
smoothly within 48 h to give the corresponding racemic
*
Corresponding authors. Tel.: +39 0405583924; fax: +39
0405583903; e-mail: felluga@dsch.units.it
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.02.019

1342
F. Felluga et al. / Tetrahedron: Asymmetry 16 (2005) 1341–1345
c-nitroesters15 3 and 4 in excellent yields (Scheme 1).
Due to the presence of the aromatic, hydrophobic sub-
stituent bonded to the stereogenic centre of these com-
pounds, we considered them good substrates for the
enzymic resolution mediated by a-chymotrypsin.
Hydrolyses of 3 and 4 proceeded with different enantio-
selectivities, as can be inferred from the values of the
respective enantiomeric ratio E,17 which was lower for
3 than for 4. Accordingly, in the former case, hydrolysis
product (S)-(ꢀ)-5 was obtained with high enantiomeric
excess (95% ee) at 23% conversion value, while the unre-
acted c-nitroester (R)-(+)-3 was recovered in an enantio-
merically pure form (99.9% ee) at 70% conversion value.
In the hydrolysis of ( )-4, owing to the high enantio-
meric ratio, at 53% conversion value, the reaction did
not practically proceed further, and both the acid (S)-
(ꢀ)-6 and the ester (R)-(+)-4 could be obtained in enan-
tiomerically pure forms, in 96% ee and 99.9% ee, respec-
tively. After 10 min, at 16% conversion value, the ee of
acid (S)-(ꢀ)-6 was slightly better (98%) but a lower yield
was obtained.
The preference of this enzyme for substrates bearing
highly hydrophobic substituents close to the ester func-
tion is in fact well known,16 and it relies on the presence
in the active site of the protein of a hydrophobic binding
pocket, in which the aromatic ring present on the sub-
strate participates in favourable hydrophobic interac-
tions with a number of apolar amino acid residues
such as Phe, Tyr and Trp.
Racemic ( )-3 and ( )-4 were treated with a-chymotryp-
sin in a buffered solution at pH 7.4. The results obtained
are summarized in the following Table 1, reporting the
enantiomeric excesses of the acidic products (S)-(ꢀ)-5
and (S)-(ꢀ)-6 and those of the recovered unreacted sub-
strates (R)-(+)-3 and (R)-(+)-4, at different conversion
values.
The dextrorotatory c-nitroesters 3 and 4 are direct pre-
cursors of (R)-(ꢀ)-b-phenylGABA and (R)-(ꢀ)-Baclo-
fen. In fact their acidic hydrolyses, carried out in a 1:1
mixture of 2 M HCl/AcOH10k under reflux, gave the
corresponding acids (R)-(+)-5 and (R)-(+)-6, which were
reduced on Nickel Raney to the desired products (R)-
(ꢀ)-9 and (R)-(ꢀ)-10, respectively. The transformations
described above were also carried out on the c-nitroac-
ids (S)-(ꢀ)-5 and (S)-(ꢀ)-6, isolated from the enzymatic
hydrolyses, thus allowing the availability of (S)-(+)-b-
phenylGABA and (S)-(+)-Baclofen.
R
R
R
iii, iv
iv
CO2H
NH2
CO2H
NO2
O
N
H
–
R = H: (S)-(+)-9
R = H: (S)-( )-5
R = H: (S)-(+)-7
R = Cl: (S)-(+)-8
–
R = Cl: (S)-(+)-10
R = Cl: (S)-( )-6
Moreover, the same substrates (R)-(+)-3 and (R)-(+)-4
were transformed into the corresponding 4-substituted
c-lactams (R)-(ꢀ)-7 and (R)-(ꢀ)-8, by reduction of the
nitro group under an atmospheric pressure of hydrogen,
in the presence of the Raney Nickel as the catalyst
(Scheme 1). The pyrrolidin-2-one derivative (R)-(ꢀ)-8
is an important lipophilic pro-drug related with GABA,
showing itself a muscle relaxant activity.18
ii
R
R
R
i
CO2Me
CO2Me
NO2
R = H: ( )-3
R = Cl: ( )-4
R = H: 1
R = Cl: 2
ii
R
R
iv
iv
CO2R1
NO2
R = H, R1 = Me: (R)-(+)-3
R = Cl, R1 = Me: (R)-(+)-4
R = H, R1 = H: (R)-(+)-5
R = Cl, R1 = H: (R)-(+)-6
3. Conclusion
CO2H
NH2
O
N
H
–
In conclusion, a convenient enantioselective synthesis of
the two pharmacologically active b-arylGABA (R)-(ꢀ)-
9 and (R)-(ꢀ)-10, together with their enantiomers, has
been developed starting from the easily available race-
mic c-nitroester precursors 3 and 4, through their enzy-
matic kinetic resolution. As already observed in a
previously reported example,16 the presence of an aro-
matic substituent on the substrates proved to be crucial
for the enantiopreference of a-chymotrypsin.
–
R = H: (R)-( )-7
R = H: (R)-( )-9
–
–
R = Cl: (R)-( )-8
R = Cl: (R)-( )-10
v
Scheme 1. Reagents and conditions: (i) CH3NO2 (5 equiv), 1,1,3,3-
tetramethylguanidine (0.2 equiv), rt, overnight; (ii) 1.0 g substrate,
0.1 g enzyme, 0.1 phosphate buffer at pH 7.4 (5 mL/mmol), rt; (iii)
CH2N2, diethyl ether; (iv) Raney Nickel, EtOH, 1 atm, rt; (v) refluxing
CH3COOH/HCl.
Table 1. Enzymatic resolutions of the c-nitroesters ( )-3 and ( )-4a
Substrate
E
Conv. (%)
Reaction time
Acid, ee (%),b [yield (%)]c
Ester, ee (%),b [yield (%)]c
3
50
23
45
70
2 h
(S)-(ꢀ)-5, 95, [18]
(S)-(ꢀ)-5, 91, [40]
(S)-(ꢀ)-5, 43, [62]
(R)-(+)-3, 29, [75]
(R)-(+)-3, 73, [48]
(R)-(+)-3, 99.9, [25]
24 h
72 h
4
120
16
53
10 min
2 h
(S)-(ꢀ)-6, 98, [15]
(R)-(+)-4, 18, [78]
(R)-(+)-4, 99.9, [42]
(S)-(ꢀ)-6, 96, [43]
a Reaction conditions: 1.0 g substrate, 0.1 g enzyme, 0.1 phosphate buffer at pH 7.4 (5 mL/mmol), room temperature.
b Enantiomeric excesses were determined by chiral HRGC.
c Yields in isolated products.

F. Felluga et al. / Tetrahedron: Asymmetry 16 (2005) 1341–1345
1343
4. Experimental
(NO2), 1596, 1496, 1455, 1437, 767, 701 (Ph); 1H
NMR, d, ppm: 7.36–7.21 (m, 5H, ArH), 4.73 (dd,
J = 12.8 and 8.0, 1H, H-4), 4.63 (dd, J = 12.8 and 7.0,
1H, H-4), 3.98 (quint, J = 7.3, 1H, H-3), 3.62 (s, 3H,
OMe), 2.77 (apparent d, J = 7.7, 2H, 2H-2); 13C
NMR, d, ppm: 171.0 (s), 138.2 (s), 129.0 (2d), 128.0
(d), 127.2 (2d), 79.6 (t), 51.9 (q), 40.1 (d), 37.45 (t);
ESI-MS (m/z): 224.1 [M+H]+, 247.0 [M+Na]+; MS (m/
z): 223 (M+, 2%), 176 (45), 118 (100), 91 (12); Anal.
Calcd for C11H13NO4: C, 59.19; H, 5.87; N, 6.27.
Found: C, 59.25; H, 5.9; N, 6.2. HRCGC tR = 45 min
(S)-enantiomer and 54 min (R)-enantiomer.
4.1. General
Mps were determined with a Buchi Apparatus and are
¨
uncorrected. IR spectra were recorded on a Jasco FT-
1
IR 200 spectrometer. H NMR and 13C NMR spectra
were run on a Jeol EX-400 (400 MHz for proton,
100.1 MHz for carbon), using deuterochloroform as a
solvent and tetramethylsilane as the internal standard,
unless otherwise stated. J values are given in Hz. Optical
rotations were determined on a Perkin Elmer Model 241
polarimeter, at 25 ꢂC. ESI-MS spectra were obtained on
a PE-API spectrometer at 5600 V by infusion of meth-
anolic solutions. Mass spectra (EI, positive ions) were
run on a VG 7070 spectrometer at 70 eV. Enzymatic
hydrolyses were performed using a pH-stat Controller
PHM290 Radiometer, Copenhagen. High Resolution
Chiral GLC (HRCGC) analyses were obtained on a Shi-
madzu 14B apparatus, using a ChiraldexTM column, type
G-TA, trifluoroacetyl-c-cyclodextrin (40 m · 0.25 mm)
(carrier gas He, 180 kPa, split 1:100, 150 ꢂC, isotherm).
TLCs were performed on Polygramꢁ Sil G/UV254 silica
gel pre-coated plastic sheets (eluent: light petroleum–
ethyl acetate). Flash chromatography was run on silica
gel, 230–400 mesh ASTM (Kieselgel 60, Merck), using
mixtures of light petroleum 40–70 ꢂC and ethyl acetate
as the eluent. CHN analyses were run on a 1106 Carlo
Erba Elemental Analyzer.
4.3.2. Methyl ( ) 3-(4-chlorophenyl)-4-nitrobutanoate
4. Compound ( )-4 was obtained in a 89% yield
after flash chromatography (eluent: light petroleum–
ethyl acetate 9:1). Mp 35 ꢂC; IR, cmꢀ1 (neat): 3030, 3002
(ArH), 1736 (CO2Et), 1556, 1378 (NO2), 1596, 1494,
1
1437, 1415, 830 (Ar); H NMR, d, ppm: 7.31 (d, 2H,
ArH), 7.17 (d, 2H, ArH), 4.71 (dd, J = 12.8 and 7.0,
1H, H-4), 4.61 (dd, J = 12.8 and 8.0, 1H, H-4), 3.97
(quint, J = 7.3, 1H, H-3), 3.63 (s, 3H, OMe), 2.77 (dd,
J = 4.4 and 7.3, 2H, 2H-2); 13C NMR, d, ppm: 170.7
(s), 136.7 (s), 133.9 (s), 128.7 (2d), 129.4 (2d), 79.05 (t),
52.0 (q), 39.4 (d), 37.3 (t); ESI-MS (m/z): 258.1
[M+H]+, 260 [M+2+H]+, 280.1 [M+Na]+; MS (m/z):
257 (M+), 210 (55), 152 (100), 115 (20); Anal. Calcd
for C11H12ClNO4: C, 51.27; H, 4.69; N, 5.44. Found:
C, 51.3; H, 4.6; N, 5.5. HRGC: tR = 139 (S)-enantiomer
and 143 min (R)-enantiomer.
Raneyꢁ 2800 nickel, slurry in water, active catalyst,
was purchased by Aldrich. a-Chymotrypsin (a-CT;
53.1 U/mg) was purchased from Fluka.
4.4. General procedure for enzymatic hydrolysis
A suspension of the c-nitroester ( )-3 (1.0 g, 4.5 mmol)
and ( )-4 (1.0 g, 3.9 mmol) in a 0.1 M KH2PO4/Na2PO4
buffer (pH 7.4) (20 mL) was hydrolyzed with a-chymo-
trypsine (0.050 g/0.500 g substrate) at room temperature
under vigorous stirring. The pH was kept at its initial
value by automatic continuous addition of 1 M NaOH.
At the desired conversion value, the unreacted (+)-c-
nitroester was extracted from the suspension with ethyl
acetate (3 · 10 mL) using a centrifuge for the separation
of the layers.
4.2. Synthesis of the reactants
Methyl 3-phenylpropenoate 1 (methyl cynnamate) and
3-(4-chlorophenyl)propenoate 2 (methyl p-chlorocynna-
mate) were obtained quantitatively from the corre-
sponding commercially available acids (Aldrich), by
esterification with MeOH used as a solvent, in the pres-
ence of trimethylchlorosilane.19
4.3. General procedure for the synthesis of methyl ( )-4-
nitro-3-phenylbutanoate 3 and methyl ( ) 3-(4-chloro-
phenyl)-4-nitrobutanoate 4
For the isolation of the (ꢀ)-c-nitroacid, the aqueous
layer was acidified to pH 2 with 2 M HCl and extracted
with chloroform (5 · 10 mL).
A mixture of nitromethane (18.3 g, 150 mmol), methyl
cynnamate 1 (4.9 g, 30 mmol) or methyl p-chloro-
cynnamate 2 (5.9 g, 30 mmol) and 1,1,3,3-tetramethyl-
guanidine14 (0.6 g, 5 mmol) was stirred at room
temperature. After 48 h, excess nitromethane was re-
moved in vacuo and the residue dissolved in diethyl
ether, washed with 5% HCl, the organic phase dried
over Na2SO4 and chromatographed on column (eluent:
light petroleum–ethyl acetate 9:1) to give 3 and 4 as pure
compounds.
4.4.1. Methyl (R)-(+)-4-nitro-3-phenylbutanoate 3. Com-
pound 3 was obtained with 99.9% ee by stopping the
enzymatic hydrolysis of ( )-3 at 70% conversion (25%
25
yield). ½aꢁ ¼ þ8:7 (c 2, CHCl3).
D
4.4.2. (S)-(ꢀ)-4-Nitro-3-phenylbutanoic acid 5. Com-
pound 5 was obtained with 95% ee by stopping the enzy-
matic hydrolysis of ( )-3 at 23% conversion (18% yield).
25
White solid, mp 103–104 ꢂC; ½aꢁ ¼ ꢀ15:2 (c 0.6,
D
MeOH); IR, cmꢀ1 (Nujol): 3510–2500 (broad, CO2H),
1711 (CO2H), 1557, 1376 (NO2), 1596, 1500, 721 (Ph);
1H NMR, d, ppm: 9.95 (broad, 1H, CO2H), 7.31 (m,
3H, ArH), 7.20 (d, 2H, ArH), 4.70 (dd, J = 12.8 and
7.0, 1H, H-4), 4.60 (dd, J = 12.8 and 8.0, 1H, H-4),
3.94 (quint, J = 7.3, 1H, H-3), 2.79 (dd, J = 4.4 and
4.3.1. Methyl ( )-4-nitro-3-phenylbutanoate 3. Com-
pound ( )-3 was obtained in a 85% yield after
purification by flash chromatography (eluent: light
petroleum–ethyl acetate 9:1). Mp 37 ꢂC; IR, cmꢀ1
(neat): 3064, 3031 (Ph), 1736 (CO2Et), 1552 and 1378

1344
F. Felluga et al. / Tetrahedron: Asymmetry 16 (2005) 1341–1345
7.3, 2H, 2H-2); 13C NMR, d, ppm: 176.6 (s), 137.9 (s),
129.1 (2d), 128.1 (d), 127.2 (2d), 79.2 (t), 39.7 (d), 37.2
(t); ESI-MS (m/z): 210.0 [M+H]+, 232.1 [M+Na]+; MS
(m/z): 162 (Mꢀ47, 73%), 134 (78), 115 (68), 105 (31),
92 (100), 78 (38); Anal. Calcd for C10H11NO4: C,
57.41; H, 5.30; N, 6.70. Found: C, 57.3; H, 5.4; N, 6.75.
(2d), 43.7 (t), 40.0. (d), 38.1 (t). ESI-MS: 180.1 [M+],
213.1 [M+Na]+. The enantiomer (S)-(+)-9, obtained
by reduction of (S)-(ꢀ)-5 (95% ee) under the same con-
25
ditions as above, had ½aꢁ ¼ þ5:8 (c 0.5, H2O, pH 7).
D
4.5.2. (R)-(ꢀ)-4-Phenylpyrrolidin-2-one 7. (R)-(ꢀ)-7
was obtained by reduction of (R)-(+)-3 (0.200 g,
0.9 mmol, 99.9% ee) over Raney Nickel under the con-
ditions described above, followed by purification on
column (eluent: ethyl acetate). The pure c-lactam
Enantiomer (R)-(+)-5 was obtained by hydrolysis of (R)-
(+)-3 having 99.9% ee, in a refluxing 1:1 mixture of
25
D
concd AcOH and 1 M HCl; ½aꢁ ¼ þ15:6 (c 1, MeOH).
(0.12 g, 82% yield) had mp 97–99 ꢂC [lit.12 101–
25
4.4.3. Methyl (R)-(+)-3-(4-chlorophenyl)-4-nitrobutano-
ate 4. Compound (R)-(+)-4 with a 99.9% ee was iso-
lated at the end of the enzymatic hydrolysis of ( )-4
104 ꢂC; lit.10e 98–99 ꢂC]; ½aꢁ ¼ ꢀ36 (c 0.5,
D
MeOH) [lit.10e [a]D = ꢀ37 (c 1.09, MeOH)]; IR, cmꢀ1
(neat): 3195 (NH), 1698 (CO); 1H NMR, d, ppm:
7.27 (m, 2H, ArH), 7.20 (m, 3H, ArH), 3.72 (dd,
J = 8.8 and 8.4, 1H, H-5), 3.64 (quint, 1 H, H-4),
3.36 (dd, J = 8.4 and 6.7, 1H, H-5), 2.65 (dd, J = 8.8
and 16.8, 1H, H-3), 2.43 (dd, J = 6.8 and 16.8, 1H,
H-3); 13C NMR, d, ppm: 178.0 (s); 142.0 (s), 128.6
(2d), 126.9 (d), 126.6 (2d), 49.5 (t), 40.1 (d), 38.35 (t).
ESI-MS 162.1 [M+H]+; MS (m/z): 161 (M+, 20%),
132 (55), 104 (100), 78 (73); Anal. Calcd for
C10H11NO: C, 74.51; H, 6.88; N, 8.69; O, 9.93. Found:
C, 74.5; H, 6.8; N, 8.7.
25
(53% conversion, 42% yield); ½aꢁ ¼ þ4:0 (c 1, CHCl3).
D
25
D
{lit.10h for the ethyl ester: ½aꢁ ¼ þ3:9 (c 0.1, CHCl3)}.
4.4.4. (S)-(ꢀ)-4-Nitro-3-(4-chlorophenyl)butanoic acid
6. Compound (S)-(ꢀ)-6 was obtained with 98% ee by
stopping the enzymatic hydrolysis of ( )ꢀ4 at 16% con-
version (15% yield). White solid, mp 78–80 ꢂC (lit10k 78–
25
79 ꢂC); ½aꢁ ¼ ꢀ10:0 (c 1, MeOH) {lit.10k [a]D = ꢀ10.1
D
(c 2, MeOH)}; IR, cmꢀ1 (Nujol): 3500–2400 (broad,
CO2H), 1710 (CO2H), 1558, 1376 (NO2), 1596, 1500,
1
803 (Ph); H NMR, d, ppm: 8.40 (broad, 1H, CO2H),
7.32 (d, 2H, ArH), 7.17 (d, 2H, ArH), 4.69 (dd,
J = 12.4 and 7.0, 1H, H-4), 4.59 (dd, J = 12.4 and 7.7,
1H, H-4), 3.94 (quint, J = 7.3, 1H, H-3), 2.79 (dd,
J = 2.9 and 7.0, 2H-2); 13C NMR, d, ppm: 176.0 (s),
136.4 (s), 134.1 (s), 129.3 (2d), 129.4 (2d), 79.0 (t), 39.2
(d), 37.2 (t); ESI-MS (m/z): 244.0 [M+H]+, 246.0
[M+2+H]+, 266.1 [M+Na]+; MS (m/z): 225 [(Mꢀ18)+,
49%], 194 (10), 155 (100), 139 (96), 103 (35); Anal. Calcd
for C10H10ClNO4: C, 49.30; H, 4.14; N, 5.75. Found: C,
49.3; H, 4.1; N, 5.65.
The opposite enantiomer (S)-(+)-7 was obtained starting
from the c-nitroacid (S)-(ꢀ)-5 (95% ee), by esterification
25
with CH2N2 to the corresponding (S)-(+)-3 and subse-
quent reduction over Nickel Raney. ½aꢁ ¼ þ21:8 (c
D
0.4, EtOH).
4.5.3. (R)-(ꢀ)-4-Amino-3-(4-chlorophenyl)butanoic acid
10. Compound (R)-(ꢀ)-10 (0.170 g, 80% yield) was ob-
tained from (R)-(+)-6 (0.250 g, 1.0 mmol) by reduction
over Nickel Raney. Its hydrochloride had mp 194–
25
D
195 ꢂC (dec); [lit.10k 195 ꢂC]; ½aꢁ ¼ ꢀ2:1 (c 1, 1 M
25
HCl) {lit.10k ½aꢁ ¼ ꢀ2:0 (c 0.60, H2O)}; IR, cmꢀ1
Enantiomer (R)-(+)-6 was obtained by hydrolysis of (R)-
(+)-4 (99.9% ee) in refluxing AcOH/1 M HCl in a 1:1 ra-
D
(Nujol): 3400–2500 (CO2H, NH3+) 1716 (CO2H), 1590,
25
D
1518 (NH3+), 1492, 1411, 758, 702 (ArH); H NMR,
1
tio for 1 h, as described in the literature.10k ½aꢁ ¼ þ10:1
(c 1.1, MeOH).
d, ppm (D2O): 7.34 (m, 4H, ArH), 3.46 (m, 2H, 2H-4),
3.27 (t, J = 10.6, 1H, H-3), 2.90 (dd, J = 4.0 and 16.2,
2H, H-2), 2.73 (dd, J = 7.3 and 16.2, 1H, H-2); 13C
NMR, d, ppm (D2O): 175.1 (s), 137.4 (s), 133.4 (s),
129.6 (2d), 129.4 (2d), 43.9 (t), 39.3 (d), 38.2 (t). ESI-
MS (m/z): 214.0 [M+], 215.0 [M+H]+, 216.0 [M+2]+
217.0 [M+2+H]+.
4.5. Reduction of the nitro compounds
4.5.1. (R)-(ꢀ)-4-Amino-3-phenylbutanoic acid 9. To a
solution of (R)-(+)-5 (0.200 g, 1 mmol, 99.9% ee) in eth-
anol (5 mL), Nickel Raney was added and the mixture
hydrogenated at atm pressure until disappearance of
the starting material (TLC, eluent: ethyl acetate). The
catalyst was filtered off on a pad of Celite and the sol-
vent removed in vacuo to give compound (R)-(ꢀ)-9.
(0.15 g, 89% yield). Mp 190–191 ꢂC [lit.10e 193 ꢂC];
The enantiomer (S)-(+)-10, obtained from (S)-(ꢀ)-6,
25
having a 98% ee, had ½aꢁ ¼ þ2:0 (c 0.5, H2O).
D
4.5.4. (R)-(ꢀ)-4-(4-Chlorophenyl)pyrrolidin-2-one 8.
(R)-(ꢀ)-8 was obtained (0.12 g, 80% yield) by reduction
of (R)-(+)-4 (0.200 g, 0.78 mmol, 99.9% ee) over Raney
Nickel under the conditions described above, followed
by purification on flash-chromatography (eluent: ethyl
acetate). White solid, mp 110 ꢂC [lit.10k 105–107 ꢂC];
25
25
D
½aꢁ ¼ ꢀ6:25 (c 0.25, H2O, pH 7); {lit.10e ½aꢁ ¼ ꢀ5:8
D
(c 0.72, H2O)}. The amino acid was converted into its
hydrochloride by treatment of a methanolic solution
25
D
with HCl(g). The hydrochloride had ½aꢁ ¼ þ2:0 (c 2,
25
1 M HCl) {lit.5 ½aꢁ ¼ þ2:3 (c 1.3, H2O, HCl)};
D
25
25
IR, cmꢀ1 (Nujol): 3000–2000 (broad, CO2H and
½aꢁ ¼ ꢀ38:0 (c 1, EtOH) {lit.10k ½aꢁ ¼ ꢀ38 (c 1.02,
D
D
1
NH3+), 1715 (CO2H), 1590, 1520 (NH3+), 1490, 1411,
EtOH)}; IR, cmꢀ1 (Nujol): 3196 (NH), 1698 (CO). H
NMR, d, ppm: 7.80 (s, 1H, NH), 7.27 (d, 2H, ArH),
7.17 (d, 2H, ArH), 3.76 (dd, J = 9.8 and 7.8, 1H, H-5),
3.63 (quint, 1H, H-4), 3.36 (dd, J = 8.4 and 7.8, 1H,
H-5), 2.71 (dd, J = 16.5 and 6.8, 1H, H-3), 2.43 (dd,
J = 16.5 and 8.4, 1H, H-3); 13C NMR, d, ppm: 177.7
1
759, 700 (ArH); H NMR, d, ppm (D2O): 7.43 (d, 2H,
ArH), 7.37 (m, 3H, ArH), 3.40 (m, 2H, 2H-4), 3.25
(quint, 1H, H-3), 2.84 (dd, J = 5.5 and 16.1, H-2), 2.75
(dd, J = 5.5 and 9.8, 2H, H-2); 13C NMR, d, ppm
(D2O): 175.3 (s), 138.4 (s), 129.4 (2d), 128.4 (d), 128.0

F. Felluga et al. / Tetrahedron: Asymmetry 16 (2005) 1341–1345
1345
8. Mann, A.; Boulanger, T.; Brandau, B.; Durant, F.;
Evrard, G.; Heaulme, M.; Desaulles, E.; Wermuth, C.
G. J. Med. Chem. 1991, 4, 1307–1313.
9. Caira, M. R.; Clauss, R.; Nassimbeni, L. R.; Scott, J. L.;
Wilderwanck, A. F. J. Chem. Soc., Perkin Trans. 2 1997,
763–768.
(s), 140.5 (s), 132.3 (s), 128.6 (2d), 127.8 (2d), 49.25 (t),
39.2 (d), 37.9 (t). ESI-MS (m/z): 196.0 [M+H]+, 198.0
[M+2+H]+, 218.0 [M+Na]+ 220.0 [M+2+Na]+; MS
(m/z): 195 (M+, 41%), 167 (10), 138 (100), 103 (74);
Anal. Calcd for C10H10ClNO: C, 61.39; H, 5.15; N,
7.16. Found: C, 61.4; H, 5.0; N, 7.3.
10. (a) Herdeis, C.; Hubmann, H. P. Tetrahedron: Asymmetry
1992, 3, 1213–1221; (b) Schoenfelder, A.; Mann, A.; Le
Coz, S. Synlett 1993, 63–64; (c) Prager, R. H.; Schafer, K.;
Hamon, D. P. C.; Massy-Westropp, R. A. Tetrahedron
1995, 51, 11465–11472; (d) Yoshifuji, S.; Kaname, M.
Chem. Pharm. Bull. 1995, 43, 1302–1306; (e) Langlois, N.;
Dahuron, N.; Wang, H.-S. Tetrahedron 1996, 52, 15117–
15126; (f) Anada, M.; Hashimoto, S. Tetrahedron Lett.
1998, 39, 79–82; (g) Resende, P.; Almeida, W. P.; Coelho,
F. Tetrahedron: Asymmetry 1999, 19, 2113–2118; (h)
Baldoli, C.; Maiorana, S.; Licandro, M.; Perdicchio, D.;
Vandoni, B. Tetrahedron: Asymmetry 2000, 11, 2007–
2014; (i) Corey, E. J.; Zhang, F.-Y. Org. Lett. 2000, 2,
4257–4259; (j) Meyer, O.; Becht, J.-M.; Helmchem, G.
Synlett 2003, 10, 1539–1541; (k) Camps, P.; Munoz-
Torrero, D.; Sanchez, L. Tetrahedron: Asymmetry 2004,
15, 2039–2044.
The opposite enantiomer was obtained starting from
(S)-(ꢀ)-6 (98% ee), by esterification with CH2N2 fol-
25
lowed by reduction over Nickel Raney, ½aꢁ ¼ þ38 (c
D
1, EtOH).
Acknowledgments
Financial support from MIUR (Rome, PRIN 2003–
2004) is gratefully acknowledged.
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