Highly Enantioselective Michael Addition of Nitroalkanes to Enones and Its Application in Syntheses of (R)-Baclofen and (R)-Phenibut

Article abstract of DOI:10.1055/s-0034-1380203

A highly enantioselective Michael addition of nitroalkanes to α,β-unsaturated ketones was developed. In the presence of a chiral primary amine-thiourea catalyst based on dehydroabietic amine, γ-nitro ketones were obtained with excellent enantioselectiviti

Full text of DOI:10.1055/s-0034-1380203

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, A–J
paper
A
X.-T. Guo et al.
Paper
Synthesis
Highly Enantioselective Michael Addition of Nitroalkanes to
Enones and Its Application in Syntheses of (R)-Baclofen and
(R)-Phenibut
Xing-Tao Guo
Jie Shen
O
R3
O
catalyst (10 mol%)
AcOH (10 mol%)
R1
NO2
catalyst:
NO2
R2
R4
+
R3
R4
R2
R1
Feng Sha*
Xin-Yan Wu*
toluene, 25 °C, 5 d
S
27 examples
75–96% yield
80–99% ee
R
R1, R2 = H, Me, -(CH2)4-
R3, R4 = Alk, Ar
N
N
H
H
NH2
R =
Key Laboratory for Advanced Materials and Institute of Fine
Chemicals, East China University of Science and Technology,
Shanghai 200237, P. R. of China
+
Cl– H3N
O2N
O
oxidation
reduction
hydrolysis
O
+
8
6
2
(
1
6
)
4
2
5
2
0
1
1
H
xinyanwu@ecust.edu.cn
OH
R
R
R = H, (R)-phenibut
R = Cl, (R)-baclofen
R = H, 98% ee
R = Cl, 98% ee
Received: 23.01.2015
Accepted after revision: 22.03.2015
Published online: 19.05.2015
DOI: 10.1055/s-0034-1380203; Art ID: ss-2015-h0046-op
ee.5g Recently, a quinine-derived primary amine has been
shown to be an efficient catalyst for the conjugate addition
of nitroalkanes to benzalacetones (91–99% ee).5h There is
still, therefore, a need to develop a highly effective organo-
catalytic Michael reaction for alkyl cinnamyl ketones.
Dehydroabietic amine (abieta-8,11,13-trien-18-amine),
a readily available rosin derivative with a well-defined chi-
ral structure, is a privileged scaffold for chiral bifunctional
organocatalysts.6–9 Although considerable progress has
been made in the application of dehydroabietic amine-
based bifunctional organocatalysts, the corresponding pri-
mary amine–thioureas have only been successfully em-
ployed in Michael addition with ketones as donors6a and in
a Diels–Alder reaction.6b We surmised that these primary
amine–thioureas might serve as efficient catalysts for the
Michael reactions of nitroalkanes. Here we report an enan-
tioselective conjugate catalytic addition of nitroalkanes to
enones.10
Initially, we selected the addition of nitromethane (2a)
to (3E)-4-(4-chlorophenyl)but-3-en-2-one (3a) as a model
reaction. To our delight, the desired product was obtained
in high yield when the reaction was catalyzed by thioureas
1a–c (Figure 1), synthesized from diaminocyclohexane
(DACH) and dehydroabietic amine (Table 1, entries 1–3).
Among these catalysts, the (1R,2R)-DACH-derived thiourea
1a gave the highest enantioselectivity (entry 1), whereas
catalyst 1c, containing a racemic DACH backbone, gave only
a 4% ee (entry 3). These results showed that dehydroabietic
amine had a slight effect on the stereocontrol of the reac-
tion and that it matched well with the (1R,2R)-DACH scaf-
fold. This observation were unlike those made by Wang and
co-workers6a with respect to the Michael reaction of ke-
tones with nitroolefins. For comparison, catalysts 1d–g
(Figure 1) lacking a rosin scaffold were examined. All the
(1R,2R)-DACH-derived catalysts gave product 4aa11 in ex-
cellent enantioselectivity (96% ee; entries 1 and 4–7). Cata-
Abstract A highly enantioselective Michael addition of nitroalkanes to
α,β-unsaturated ketones was developed. In the presence of a chiral pri-
mary amine–thiourea catalyst based on dehydroabietic amine, γ-nitro
ketones were obtained with excellent enantioselectivities (up to 99%
ee) and in up to 96% yield. This protocol was successfully applied in
asymmetric syntheses of (R)-baclofen and (R)-phenibut with high yields
and excellent enantioselectivities.
Key words chiral primary amine–thiourea, dehydroabietic amine, en-
antioselective Michael addition, nitroalkanes, α,β-unsaturated ketones
As versatile building blocks for natural and synthetic bi-
ologically active molecules, γ-nitro ketones are of signifi-
cant interest in organic chemistry.1 The Michael addition of
nitroalkanes to α,β-unsaturated ketones is a useful way of
obtaining γ-nitro ketones.2 In recent decades, many chiral
organocatalysts have been used in asymmetric conjugate
additions of nitroalkanes to chalcones3 or cyclic enones.4
However, fewer studies on alkyl cinnamyl ketones have
been reported,4f,j,l,m,5 and only a few organocatalytic sys-
tems provided high enantioselectivities (≥90% ee) for these
Michael acceptors.5d,5f–h For example, in 2009, Wang and co-
workers5d reported a Michael addition of nitroalkanes to al-
kyl cinnamyl ketones catalyzed by a chiral diaminocyclo-
hexane-derived primary amine–thiourea bearing a 3,5-
bis(trifluoromethyl)phenyl group; this reaction gave the
desired products in 92–99% ee. Later, chiral primary and
secondary diamines derived from camphor and phenylala-
nine were shown to have a high efficiency (90–96% ee) in
the reactions of acetocinnamones.5f The intramolecular
Michael reactions of (1E)-1-aryl-6-nitrohex-1-en-3-ones in
the presence of a quinine-derived primary amine as a chiral
organocatalyst gave the corresponding adducts in 95–97%
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–J

B
X.-T. Guo et al.
Paper
Synthesis
S
S
N
H
N
H
NH
NH
1b
H
H
NH2
NH2
1a
S
S
Ph
N
N
N
NH
H
H
H
H
NH2
NH2
trans
1c
1d
CF3
S
S
S
Bn
Ph
N
N
N
N
F3C
N
N
H
H
H
H
H
H
NH2
NH2
NH2
1e
Figure 1 Structures of chiral bifunctional organocatalysts 1a–g
1f
1g
Table 1 Screening of Catalysts for a Michael Reaction of Nitromethanea
lysts 1d and 1e, bearing different chiral phenylethyl groups,
gave the product in good yields (74% and 70%, respectively),
showing that a chiral phenylethyl moiety adjacent to the
thiourea has a limited effect on the reactivity and that the
enantioselectivity is depended on the chiral DACH back-
bone. When thiourea 1f containing a benzyl group was
used as the organocatalyst, the Michael reaction gave only a
69% yield. Catalyst 1g gave the product in 82% yield, which
was lower than that obtained with catalyst 1a (entries 7
and 1). We therefore selected organocatalyst 1a for our sub-
sequent investigations.
Next, we examined the effects of various solvents (Table
2). When toluene, a xylene, or mesitylene was used as the
solvent, the Michael product was obtained in a good yield
(81–88%) and an excellent ee (95–96%). In contrast, other
solvents such as dichloromethane, ethyl acetate, tetrahy-
drofuran, acetonitrile, nitromethane, and dimethyl sulfox-
ide gave slow conversions and yields of 13–72%; however,
high enantioselectivities were observed in these solvents
(other than dimethyl sulfoxide). Toluene was therefore se-
lected as the optimal solvent for the Michael reaction.
We then examined various additives in an attempt to
accelerate the reaction (Table 3). Additives had various ef-
fects on the rate and yield of the reaction, but had no ob-
servable effects on its enantioselectivity. The reaction gave
a lower conversion when formic acid or phenylacetic acid
was used (Table 3, entries 2 and 5). Encouragingly, the addi-
tion of acetic acid led to a shorter reaction time and a high-
er yield (entry 3). It appeared that propionic acid or the ba-
sic additive triethylamine had a limited effect on the reac-
tion (entries 4 and 8). With benzoic acid, the chemical yield
was maintained but the reaction was completed in a short-
er time (entry 6). Moreover, the stronger acid 4-toluenesul-
Cl
O
1a–g (20 mol%)
MeNO2
+
O
toluene, 25 °C, 7 d
Cl
NO2
2a
3a
4aa
eec (%)
Entry
Catalyst
Yieldb (%)
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
88
86
86
74
70
69
82
96
–88
4
96
96
96
96
1g
a Reaction conditions: MeNO2 (2a; 3.0 mmol), enone 3a (0.3 mmol), catalyst
(0.06 mmol), toluene (2 mL), 25 °C, 7 d.
b Isolated yield.
c Determined by chiral HPLC analysis.
fonic acid had a markedly detrimental effect on the trans-
formation, and no product was obtained (entry 7). The use
of the correct additive is therefore critical for both the rate
and yield of the reaction, and acetic acid was selected as the
additive for subsequent screening studies.
Other aspects of the reaction conditions, including the
substrate concentration, temperature, catalyst loading, and
amount of nitromethane were then investigated (Table 4).
When the concentration of 3a was increased to 0.3 M, the
reaction was completed in a shorter time but with a re-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–J

C
X.-T. Guo et al.
Paper
Synthesis
Table 2 Solvent Screening for a Michael Reaction of Nitromethanea
duced yield (Table 4, entries 1 and 2). Conversely, a lower
substrate concentration (0.1 M) gave an obviously increase
in reaction time (entry 3). Although the shortest reaction
time was observed when the reaction was carried out at
40 °C, the yield dropped markedly and byproducts were ob-
tained (entry 4). At 0 °C, on the other hand, the reaction be-
came sluggish and required a longer time to give a high
yield (entry 5). Reducing the catalyst loading resulted in a
lower reaction rate (entries 6 and 7). The desired product
was obtained in excellent yield when the amount of nitro-
methane relative to that of the enone 3a was increased to
15 equivalents, but a further increase in the amount of ni-
tromethane did not improve the yield any further (entries 8
and 9). In terms of the yield and enantioselectivity, the op-
timal reaction conditions were selected as a substrate con-
centration of 0.15 M, a temperature of 25 °C, a catalyst
loading of 10 mol%, and 15 equivalents of nitromethane.
Cl
O
1a (20 mol%)
MeNO2
+
solvent, 25 °C, 7 d
O
Cl
NO2
2a
3a
4aa
Entry
Solvent
Yieldb (%)
eec (%)
1
2
toluene
o-xylene
m-xylene
p-xylene
mesitylene
CH2Cl2
88
81
86
86
88
72
65
46
32
45
13
96
95
95
95
95
97
96
95
93
90
6
3
4
5
6
7
EtOAc
Table 4 Further Optimization of the Reaction Conditions for the Mi-
8
THF
chael Reactiona
9
MeCN
Cl
10
11
MeNO2
DMSO
O
a Reaction conditions: MeNO2 (2a; 3.0 mmol), enone 3a (0.3 mmol), catalyst
1a (0.06 mmol), solvent (2 mL), 25 °C, 7 d.
b Isolated yield.
1a, AcOH
O
MeNO2
+
toluene
NO2
Cl
c Determined by chiral HPLC analysis.
2a
3a
4aa
eec (%)
Table 3 The Effect of Various Additives on the Michael Reactiona
Entry
1a (mol%)
Time (d)
Yieldb (%)
1
20
20
20
20
20
15
10
10
10
5
94
90
93
88
90
92
88
94
92
96
96
95
96
96
97
97
97
97
Cl
O
2d
3e
4f
5g
6
3
1a (20 mol%)
additives (20 mol%)
6.5
1
MeNO2
+
O
toluene, 25 °C
Cl
NO2
9
2a
3a
Additive
4aa
eec (%)
6
7
8
Entry
Time (d)
Yieldb (%)
8h
9i
5
1
2
3
4
5
6
7
8
–
7
88
96
96
4
HCO2H
AcOH
EtCO2H
BnCO2H
PhCO2H
TsOH
7
70
a Reaction conditions: MeNO2 (2a; 3.0 mmol), enone 3a (0.3 mmol, 0.15 M),
catalyst 1a, AcOH (0.06 mmol), toluene (2 mL), 25 °C (unless otherwise
stated).
5
94
96
7
89
96
b Isolated yield.
c Determined by chiral HPLC analysis.
d The concentration of 3a was 0.3 M.
e The concentration of 3a was 0.1 M.
f The temperature was 40 °C.
7
72
96
4.5
7
86
96
trace
89
n.d.d
96
g The temperature was 0 °C.
h MeNO2 (15 equiv) relative to enone 3a was used.
i MeNO2 (20 equiv) relative to enone 3a was used.
Et3N
7
a Reaction conditions: MeNO2 (2a; 3.0 mmol), enone 3a (0.3 mmol), catalyst
1a (0.06 mmol), additive (0.06 mmol), toluene (2 mL), 25 °C.
b Isolated yield.
By using the optimal reaction conditions, the substrate
scope with regard to the α,β-unsaturated ketone was then
investigated with nitromethane as the donor (Table 5, en-
tries 1–17). The reaction was only slightly sensitive to elec-
tronic effects of the substituents on the phenyl group of the
α,β-unsaturated ketones, and the desired products were ob-
c Determined by chiral HPLC analysis.
d Not determined.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–J

D
X.-T. Guo et al.
Paper
Synthesis
tained in excellent yields and enantioselectivities (entries
1–9). Substrate 3 bearing a 2-furyl heteroaromatic group
also performed well, giving product 4aj in 86% yield and
98% ee (entry 10). Other alkyl cinnamyl ketones and ali-
phatic acyclic enones also provided excellent stereoselectiv-
ities, despite requiring longer reaction time or higher reac-
tion temperature as a result of steric hindrance or low reac-
tivity (entries 11–15). Moreover, cyclohex-2-en-1-one was
well tolerated, giving the desired product in 75% yield and
95% ee (entry 17). However, chalcone gave the correspond-
ing product 4ap with only 80% ee, even when the catalyst
loading was increased to 20 mol%; this was probably due to
an electronic effect of the phenyl group attached to the ke-
tone (entry 16).
Our further explorations of the scope of the reaction fo-
cused on changing the structure of the nitroalkane. When
nitroethane was used as the Michael donor, the syn-diaste-
reomer of the product was obtained in 94% ee, whereas the
anti-diastereomer was obtained with 84% ee; the reaction
therefore gave a high yield but a poor diastereoselectivity
(Table 5, entry 18). Other, more sterically hindered, nitroal-
kanes, such as 2-nitropropane or nitrocyclopentane, were
still well tolerated and gave the desired products with high
yields and excellent enantioselectivities (entries 19–27). On
the basis of the optical rotations reported in the litera-
ture,3d,4f,j,5d,f,h,12 all the products other than 4aj–al, 4aq, 4bh,
and 4bi were assigned as having an (R)-absolute configura-
tion.
The reactions of several enones were examined under
the optimal reaction conditions, but with catalyst 1g. Cata-
lyst 1a gave higher yields than catalyst 1g when (1E)-1-
phenylpent-1-en-3-one or (1E)-4-methyl-1-phenylpent-1-
en-3-one was used as the Michael acceptor (Table 5; entries
13 and 14 versus 28 and 29). When the reaction time was
reduced to 1.5 days, both 1a and 1g gave products 4aa, 4ag,
and 4ap in similar yields and enantioselectivities, but cata-
lyst 1a gave the cyclic γ-nitro ketone 4aq in a higher yield
than did catalyst 1g.13 These results show that catalyst 1a is
a better catalyst than 1g for the Michael reactions of ni-
troalkanes with enones.
An important synthetic application of this method is the
transformation of the γ-nitro ketones 4 into the corre-
sponding optically active γ-aminobutyric acids, such as (R)-
baclofen and (R)-phenibut. Baclofen and phenibut are ther-
apeutically useful as agonists of γ-aminobutyric acid type-
B receptors, and their (R)-enantiomers are the biological ac-
tive forms.14,15 In recent decades, syntheses of (R)-baclofen
and (R)-phenibut by using asymmetric catalysts have been
reported by several groups,16,17 and organocatalysis is
among the most powerful methods for generating the ste-
reocenters of the two drugs.16 However, few highly enantio-
selective syntheses (≥95% ee) of chiral intermediates of
(R)-baclofen and (R)-phenibut by using organocatalysts
have been reported.16c,h Although Wang and co-workers16c
Table 5 Substrate Scope of the Michael Addition of Nitroalkanes and
Enonesa
O
R3
1a (10 mol%)
AcOH (10 mol%)
O
R1
NO2
NO2
R2
R4
R3
R4
+
R2
toluene, 25 °C, 5 d
R1
2
3
4
Entry R1
R2
R3
R4
Me
Yieldb (%)
eec (%)
1
2
H
H
4-ClC6H4
2-ClC6H4
3-ClC6H4
4-NO2C6H4
4-FC6H4
4-BrC6H4
C6H5
94 (4aa)
92 (4ab)
90 (4ac)
87 (4ad)
94 (4ae)
95 (4af)
96 (4ag)
93 (4ah)
90 (4ai)
86 (4aj)
86 (4ak)
92 (4al)
97
97
97
96
97
97
97
97
97
98
97
97
99
98
98
80
95
94 (84)
92
94
91
95
95
95
95
95
92
99
98
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
3
H
H
4
H
H
5
H
H
6
H
H
7
H
H
8
H
H
4-MeC6H4
4-MeOC6H4
2-furyl
9
H
H
10
11d
12d
13e
14d
15d
16f
17g
18h
19
20
21
22
23
24
25d
26d
27
28e,i
29d,i
H
H
H
H
n-C5H11
(CH2)2Ph
Ph
H
H
H
H
91 (4am)
83 (4an)
85 (4ao)
75 (4ap)
75 (4aq)
96 (4ba)
89 (4bb)
89 (4bc)
90 (4bd)
92 (4be)
87 (4bf)
85 (4bg)
82 (4bh)
88 (4bi)
93 (4bj)
54 (4am)
45 (4an)
H
H
Ph
i-Pr
i-Pr
Ph
H
H
4-ClC6H4
Ph
H
H
H
H
(CH2)3
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Me
Me
Me
Me
Me
Me
Me
Me
4-FC6H4
4-ClC6H4
4-BrC6H4
Ph
4-MeC6H4
4-MeOC6H4
n-C5H11
(CH2)2Ph
Ph
(CH2)4
H
H
H
Ph
H
Ph
i-Pr
a Reaction conditions: nitroalkane 2 (4.5 mmol), enone 3 (0.3 mmol), cata-
lyst 1a (0.03 mmol), AcOH (0.03 mmol), toluene (2 mL), 25 °C, 5 d (unless
otherwise stated).
b Isolated yield.
c Determined by chiral HPLC analysis.
d Temperature 40 °C.
e Reaction time 9 d.
f 1a (20 mol%) and AcOH (20 mol%) were used, and the reaction time was
10 d.
g Reaction time 3 d.
h Total yield for both diastereomers. The dr (syn/anti) was 4:3, and the ee of
the anti-diastereomer is shown in parentheses.
i Catalyst 1g (10 mol%).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–J

E
X.-T. Guo et al.
Paper
Synthesis
approached (R)-baclofen by a three-step approach involving
an enantioselective Michael addition of nitromethane to
(2E)-3-(4-chlorophenyl)acrylaldehyde (96% ee), their over-
all yield was unsatisfactory (50%). Kokotos and co-work-
ers16h completed a synthesis of (R)-baclofen beginning with
a highly stereoselective (>99% ee) conjugate addition of ace-
tophenone to 1-chloro-4-[(E)-2-nitrovinyl]benzene, but
they obtained only a 55% overall yield for the initial two
steps. To the best of our knowledge, a synthesis of γ-amino-
butyric acids from a 1-alkyl-3-aryl-4-nitrobutan-1-one as a
key precursor has not previously been described.
We began our synthesis with a Bayer–Villiger oxidation
of products 4an and 4ao to give the corresponding γ-nitro
esters 5 in 93% and 92% yield, respectively, with retained
enantioselectivity (Scheme 1). Reduction of the nitro group
of compounds 5 gave the corresponding γ-amino esters 6 in
88% and 90% yield, respectively. Subsequent hydrolysis of 6
gave (R)-baclofen and (R)-phenibut in 95% and 93% yield,
respectively. Thus, the four-step synthesis starting from ni-
tromethane gave (R)-baclofen and (R)-phenibut in high
yields (65% overall) and excellent enantioselectivities.
corded on a Nicolet Magna-I 550 spectrometer. High-resolution mass
spectra were recorded on a Waters Micromass GCT Premier spec-
trometer with an EI resource. Optical rotations were measured on a
WZZ-2A digital polarimeter at the wavelength of the sodium D-line
(589 nm). TLC was performed on 10–40 μm silica gel plates. Column
chromatography was carried out on silica gel (300–400 mesh) with
EtOAc–PE as eluent. HPLC analysis was performed on Waters equip-
ment using a Daicel Chiralcel OD-H column, a Daicel Chiralpak AS-H
column, or a Daicel Chiralpak AD-H column. CH2Cl2, EtOAc, MeCN, and
DMSO were freshly distilled from CaH2. THF, toluene, o-xylene, m-xy-
lene, p-xylene, and mesitylene were freshly distilled from sodium–
benzophenone. Nitroalkanes were commercial products of analytical
grade and were used without purification. The α,β-unsaturated ke-
tones were prepared by the reported methods.18
Nitro Ketones 4aa–aq and 4ba–bj; General Procedure
Nitroalkane 2 (4.5 mmol) was added to a solution of catalyst 1a (0.03
mmol), AcOH (0.03 mmol), and enone 3 (0.3 mmol) in toluene (2 mL)
at 25 °C, and the mixture was stirred at 25 °C until the reaction was
complete (TLC). The solvent was removed under reduced pressure
and the residue was purified by column chromatography.
(R)-4-(4-Chlorophenyl)-5-nitropentan-2-one (4aa)12
White solid; yield: 68.1 mg (94%; 97% ee); [α]D25 –10.2 (c 0.68, CHCl3).
O2N
HPLC: [Daciel Chiralpak AD-H, λ = 220 nm, eluent: i-PrOH–hexane
(15:85), flow rate: 0.9 mL/min]; tR = 11.0 min (minor), 12.5 min (ma-
jor).
O2N
m-CPBA, TFA
O
O
CH2Cl2, reflux, 48 h
O
1H NMR (400 MHz, CDCl3): δ = 7.30 (d, J = 8.4 Hz, 2 H), 7.16 (d, J = 8.4
Hz, 2 H), 4.68 (dd, J = 6.6, 12.6 Hz, 1 H), 4.57 (dd, J = 7.8, 12.6 Hz, 1 H),
4.03–3.95 (m, 1 H), 2.89 (dd, J = 2.4, 7.2 Hz, 2 H), 2.13 (s, 3 H).
R
R
5a, R = H, 93% yield, 98% ee
5b, R = Cl, 92% yield, 98% ee
4an, R = H, 98% ee
4ao, R = Cl, 98% ee
(4R)-4-(2-Chlorophenyl)-5-nitropentan-2-one (4ab)12
Colorless oil; yield: 66.8 mg (92%; 97% ee); [α]D25 –18.2 (c 0.67, CHCl3).
NiCl2·6H2O
NaBH4, EtOH
0 °C, 2 h
HPLC: [Daciel Chiralpak AS-H, λ = 220 nm, eluent: i-PrOH–hexane
(10:90), flow rate: 0.9 mL/min]; tR = 20.7 min (minor), 23.0 min (ma-
jor).
+
Cl– H3N
O
H2N
O
1H NMR (400 MHz, CDCl3): δ = 7.41–7.39 (m, 1 H), 7.27–7.19 (m, 3 H),
4.78–4.66 (m, 2 H), 4.48–4.44 (m, 1 H), 3.09–2.93 (m, 2 H), 2.16 (s, 3
H).
6 M HCl
100 °C, 20 h
OH
O
R
R
(4R)-4-(3-Chlorophenyl)-5-nitropentan-2-one (4ac)12
Colorless oil; yield: 65.2 mg (90%; 97% ee); [α]D25 –7.8 (c 0.65, CHCl3).
R = H, (R)-phenibut, 95% yield
R = Cl, (R)-baclofen, 93% yield
6a, R = H, 88% yield
6b, R = Cl, 90% yield
HPLC: [Daciel Chiralpak AS-H, λ = 220 nm, eluent: i-PrOH–hexane
(10:90), flow rate: 0.9 mL/min]; tR = 31.2 min (minor), 47.9 min (ma-
jor).
Scheme 1 Asymmetric syntheses of (R)-baclofen and (R)-phenibut
1H NMR (300 MHz, CDCl3): δ = 7.28–7.20 (m, 3 H), 7.13–7.10 (m, 1 H),
4.68 (dd, J = 6.3, 12.6 Hz, 1 H), 4.55 (dd, J = 6.3, 12.6 Hz, 1 H), 4.03–
3.93 (m, 1 H), 2.90 (d, J = 7.2 Hz, 2 H), 2.12 (s, 3 H).
In summary, a highly enantioselective Michael addition
of nitroalkanes to α,β-unsaturated ketones was achieved by
using a chiral primary amine–thiourea catalyst 1a based on
dehydroabietic amine. The reaction has a wide substrate
scope, providing chiral γ-nitro ketones in excellent enantio-
selectivities (≤99% ee) and high yields (≤96%). Moreover,
this synthetic method was successfully applied in asym-
metric syntheses of (R)-baclofen and (R)-phenibut.
(4R)-5-Nitro-4-(4-nitrophenyl)pentan-2-one (4ad)5d
25
Pale-yellow solid; yield: 65.4 mg (87%; 96% ee); [α]D –10.7 (c 0.65,
CHCl3).
HPLC: [Daciel Chiralpak AD-H, λ = 254 nm, eluent: i-PrOH–hexane
(10:90), flow rate: 0.9 mL/min]; tR = 43.8 min (minor), 60.0 min (ma-
jor).
1H NMR (400 MHz, CDCl3): δ = 8.21 (d, J = 8.4 Hz, 2 H), 7.45 (d, J = 8.4
Hz, 2 H), 4.77 (dd, J = 6.3, 12.6 Hz, 1 H), 4.66 (dd, J = 8.1, 12.6 Hz, 1 H),
4.19–4.12 (m, 1 H), 3.04–2.93 (m, 2 H), 2.17 (s, 3 H).
1H NMR and 13C NMR spectra were recorded on a Varian 300 or a
Bruker 400 spectrometer with CDCl3 or D2O as solvent. Chemical
shifts are reported relative to TMS (δ = 0.00 ppm). IR spectra were re-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–J

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Synthesis
(4R)-4-(4-Fluorophenyl)-5-nitropentan-2-one (4ae)5d
(4S)-4-(Nitromethyl)nonan-2-one (4ak)5d
25
Pale-yellow oil; yield: 63.6 mg (94%; 97% ee); [α]D –9.1 (c 0.64,
Colorless oil; yield: 52.0 mg (86%; 97% ee); [α]D25 +2.3 (c 0.52, CHCl3).
CHCl3).
HPLC: [Daciel Chiralpak AD-H, λ = 220 nm, eluent: i-PrOH–hexane
(1:99), flow rate: 0.9 mL/min]; tR = 12.2 min (minor), 13.8 min (ma-
jor).
1H NMR (400 MHz, CDCl3): δ = 4.37 (d, J = 5.2 Hz, 2 H), 2.58–2.44 (m, 3
H), 2.10 (s, 3 H), 1.29–1.18 (m, 8 H), 0.81 (t, J = 6.8 Hz, 3 H).
HPLC: [Daciel Chiralpak AD-H, λ = 220 nm, eluent: i-PrOH–hexane
(10:90), flow rate: 0.9 mL/min]; tR = 14.5 min (minor), 16.2 min (ma-
jor).
1H NMR (400 MHz, CDCl3): δ = 7.24–7.20 (m, 2 H), 7.06–7.02 (m, 2 H),
4.70 (dd, J = 6.6, 12.3 Hz, 1 H), 4.59 (dd, J = 7.8, 12.3 Hz, 1 H), 4.06–
3.98 (m, 1 H), 2.91 (d, J = 7.2 Hz, 2 H), 2.15 (s, 3 H).
(4S)-4-(Nitromethyl)-6-phenylhexan-2-one (4al)5d
25
Pale-yellow oil; yield: 64.9 mg (92%; 97% ee); [α]D –6.2 (c 0.64,
CHCl3).
(4R)-4-(4-Bromophenyl)-5-nitropentan-2-one (4af)5d
25
Pale-yellow solid; yield: 81.5 mg (95%; 97% ee); [α]D +8.9 (c 0.81,
HPLC: [Daciel Chiralpak AS-H, λ = 220 nm, eluent: i-PrOH–hexane
(10:90), flow rate: 0.9 mL/min]; tR = 16.0 min (minor), 17.8 min (ma-
jor).
1H NMR (400 MHz, CDCl3): δ = 7.30–7.26 (m, 2 H), 7.21–7.14 (m, 3 H),
4.49–4.47 (m, 2 H), 2.73–2.52 (m, 5 H), 2.14 (s, 3 H), 1.75–1.68 (m, 2
H).
CHCl3).
HPLC: [Daciel Chiralpak AD-H, λ = 220 nm, eluent: i-PrOH–hexane
(10:90), flow rate: 0.9 mL/min]; tR = 16.2 min (minor), 18.6 min (ma-
jor).
1H NMR (400 MHz, CDCl3): δ = 7.47 (d, J = 8.0 Hz, 2 H), 7.12 (d, J = 8.4
Hz, 2 H), 4.70 (dd, J = 6.6, 12.6 Hz, 1 H), 4.59 (dd, J = 8.1, 12.6 Hz, 1 H),
4.03–3.96 (m, 1 H), 2.91 (d, J = 7.2 Hz, 2 H), 2.15 (s, 3 H).
(5R)-6-Nitro-5-phenylhexan-3-one (4am)5d
Colorless oil; yield: 60.5 mg (91%; 99% ee); [α]D25 –10.2 (c 0.60, CHCl3).
(4R)-5-Nitro-4-phenylpentan-2-one (4ag)5d
White solid; yield: 59.3 mg (96%; 97% ee); [α]D25 –5.3 (c 0.59, CHCl3).
HPLC: [Daciel Chiralpak AS-H, λ = 220 nm, eluent: i-PrOH–hexane
(1:99), flow rate: 0.9 mL/min]; tR = 15.7 min (minor), 19.1 min (ma-
jor).
1H NMR (300 MHz, CDCl3): δ = 7.36–7.30 (m, 3 H), 7.26–7.20 (m, 2 H),
4.70 (dd, J = 6.9, 12.3 Hz, 1 H), 4.60 (dd, J = 7.8, 12.3 Hz, 1 H), 4.08–
3.98 (m, 1 H), 2.88 (d, J = 7.2 Hz, 2 H), 2.46–2.29 (m, 2 H), 1.00 (t,
J = 7.2 Hz, 3 H).
HPLC: [Daciel Chiralpak AD-H, λ = 220 nm, eluent: i-PrOH–hexane
(10:90), flow rate: 0.9 mL/min]; tR = 12.7 min (minor), 13.6 min (ma-
jor).
1H NMR (400 MHz, CDCl3): δ = 7.35–7.20 (m, 5 H), 4.69 (dd, J = 6.9,
12.3 Hz, 1 H), 4.59 (dd, J = 7.8, 12.3 Hz, 1 H), 4.04–3.97 (m, 1 H), 2.91
(d, J = 6.9 Hz, 2 H), 2.12 (s, 3 H).
(5R)-2-Methyl-6-nitro-5-phenylhexan-3-one (4an)5d
(4R)-5-Nitro-4-(4-tolyl)pentan-2-one (4ah)5d
White solid; yield: 61.7 mg (93%), 97% ee; [α]D25 –3.8 (c 0.62, CHCl3).
25
Pale-yellow oil; yield: 88.0 mg (83%; 98% ee); [α]D –18.2 (c 0.88,
CHCl3).
HPLC: [Daciel Chiralpak AD-H, λ = 220 nm, eluent: i-PrOH–hexane
(10:90), flow rate: 0.9 mL/min]; tR = 11.5 min (minor), 12.7 min (ma-
jor).
HPLC: [Daciel Chiralpak AS-H, λ = 220 nm, eluent: i-PrOH–hexane
(10:90), flow rate: 0.9 mL/min]; tR = 9.4 min (minor), 12.2 min (ma-
jor).
1H NMR (400 MHz, CDCl3): δ = 7.14 (dd, J = 8.0, 14.8 Hz, 4 H), 4.69 (dd,
J = 6.9, 12.3 Hz, 1 H), 4.59 (dd, J = 7.8, 12.3 Hz, 1 H), 4.03–3.95 (m, 1
H), 2.91 (d, J = 7.2 Hz, 2 H), 2.34 (s, 3 H), 2.14 (s, 3 H).
1H NMR (400 MHz, CDCl3): δ = 7.33–7.20 (m, 5 H), 4.69 (dd, J = 7.2,
12.4 Hz, 1 H), 4.60 (dd, J = 8.4, 12.4 Hz, 1 H), 4.05–3.98 (m, 1 H), 2.97–
2.85 (m, 2 H), 2.57–2.46 (m, 1 H), 1.04 (d, J = 6.8 Hz, 3 H), 0.99 (d,
J = 6.8 Hz, 3 H).
(4R)-4-(4-Methoxyphenyl)-5-nitropentan-2-one (4ai)5d
White solid; yield: 64.0 mg (90%; 97% ee); [α]D25 +7.7 (c 0.64, CHCl3).
(5R)-5-(4-Chlorophenyl)-2-methyl-6-nitrohexan-3-one (4ao)
25
Pale-yellow oil; yield: 103.1 mg (85%; 98% ee); [α]D –21.7 (c 1.03,
HPLC: [Daciel Chiralpak AD-H, λ = 220 nm, eluent: i-PrOH–hexane
(10:90), flow rate: 0.9 mL/min]; tR = 17.9 min (minor), 19.9 min (ma-
jor).
1H NMR (400 MHz, CDCl3): δ = 7.15 (d, J = 8.8 Hz, 2 H), 6.87 (d, J = 8.8
Hz, 2 H), 4.68 (dd, J = 6.9, 12.3 Hz, 1 H), 4.57 (dd, J = 7.8, 12.3 Hz, 1 H),
4.01–3.94 (m, 1 H), 3.80 (s, 3 H), 2.90 (d, J = 7.2 Hz, 2 H), 2.13 (s, 3 H).
CHCl3).
HPLC: [Daciel Chiralpak AS-H, λ = 220 nm, eluent: i-PrOH–hexane
(10:90), flow rate: 0.9 mL/min]; tR = 11.0 min (minor), 18.1 min (ma-
jor).
IR (KBr, film): 2972, 2933, 1712, 1552, 1492, 1379, 1093, 1014, 829,
542 cm–1
.
(4S)-4-(2-Furyl)-5-nitropentan-2-one (4aj)5d
1H NMR (400 MHz, CDCl3): δ = 7.30–7.27 (m, 2 H), 7.18–7.15 (m, 2 H),
4.68 (dd, J = 6.8, 12.4 Hz, 1 H), 4.58 (dd, J = 8.0, 12.4 Hz, 1 H), 4.04–
3.97 (m, 1 H), 2.89 (dd, J = 2.0, 6.8 Hz, 2 H), 2.55–2.49 (m, 1 H), 1.05 (d,
J = 7.2 Hz, 3 H), 1.00 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 211.2, 137.6, 133.6, 129.2, 128.8, 79.2,
42.9, 41.2, 38.4, 17.9.
25
Pale-yellow oil; yield: 50.7 mg (86%; 98% ee); [α]D +9.0 (c 0.51,
CHCl3).
HPLC: [Daciel Chiralpak AD-H, λ = 220 nm, eluent: i-PrOH–hexane
(10:90), flow rate: 0.9 mL/min]; tR = 12.4 min (minor), 14.1 min (ma-
jor).
1H NMR (400 MHz, CDCl3): δ = 7.36–7.34 (m, 1 H), 6.32–6.30 (m, 1 H),
6.17–6.15 (m, 1 H), 4.71–4.68 (m, 2 H), 4.15–4.09 (m, 1 H), 3.03–2.89
(m, 2 H), 2.20 (s, 3 H).
HRMS (EI): m/z calcd for C13H16ClNO3: 269.0819; found: 269.0816.
(3R)-4-Nitro-1,3-diphenylbutan-1-one (4ap)3d
White solid; yield: 76.8 mg (75%; 80% ee); [α]D25 +5.2 (c 0.76, CHCl3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–J

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Synthesis
HPLC: [Daciel Chiralpak AS-H, λ = 254 nm, eluent: i-PrOH–hexane
(10:90), flow rate: 0.9 mL/min]; tR = 20.5 min (minor), 26.6 min (ma-
jor).
(4R)-4-(4-Bromophenyl)-5-methyl-5-nitrohexan-2-one(4bd)5h
25
Pale-yellow solid; yield: 84.8 mg (90%; 91% ee); [α]D +27.2 (c 0.84,
CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.92 (d, J = 7.8 Hz, 2 H), 7.58 (t, J = 7.2
Hz, 1 H), 7.46 (t, J = 7.8 Hz, 2 H), 7.34 (t, J = 7.2 Hz, 2 H), 7.30–7.27 (m,
3 H), 4.84 (dd, J = 6.4, 12.8 Hz, 1 H), 4.70 (dd, J = 4.0, 12.4 Hz, 1 H),
4.29–4.19 (m, 1 H), 3.52–3.40 (m, 2 H).
HPLC: [Daciel Chiralpak AS-H, λ = 220 nm, eluent: i-PrOH–hexane
(10:90), flow rate: 0.6 mL/min]; tR = 23.1 min (major), 25.9 min (mi-
nor).
1H NMR (400 MHz, CDCl3): δ = 7.35 (d, J = 8.4 Hz, 2 H), 7.00 (d, J = 8.4
Hz, 2 H), 3.81 (dd, J = 3.6, 10.8 Hz, 1 H), 2.97 (dd, J = 10.8, 17.6 Hz, 1
H), 2.65 (dd, J = 3.6, 17.6 Hz, 1 H), 1.96 (s, 3 H), 1.46 (s, 3 H), 1.40 (s, 3
H).
(3S)-3-(Nitromethyl)cyclohexanone (4aq)5h
Colorless oil; yield: 35.2 mg (75%; 95% ee); [α]D25 +8.2 (c 0.35, CHCl3).
HPLC: [Daciel Chiralpak AD-H, λ = 220 nm, eluent: i-PrOH–hexane
(10:90), flow rate: 0.9 mL/min]; tR = 21.2 min (minor), 23.3 min (ma-
jor).
(4R)-5-Methyl-5-nitro-4-phenylhexan-2-one (4be)5h
Colorless oil; yield: 65.1 mg (92%; 95% ee); [α]D25 +35.2 (c 0.65, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 4.40–4.35 (m, 2 H), 2.69–2.63 (m, 1 H),
2.55–2.46 (m, 2 H), 2.35–2.27 (m, 1 H), 2.22–2.13 (m, 2 H), 2.03–1.98
(m, 1 H), 1.82–1.72 (m, 1 H), 1.59–1.49 (m, 1 H).
HPLC: [Daciel Chiralpak AS-H, λ = 220 nm, eluent: i-PrOH–hexane
(10:90), flow rate: 0.9 mL/min]; tR = 12.0 min (major), 16.9 min (mi-
nor).
1H NMR (400 MHz, CDCl3): δ = 7.32–7.25 (m, 3 H), 7.20–7.18 (m, 2 H),
3.94 (dd, J = 3.6, 10.4 Hz, 1 H), 3.10 (dd, J = 10.4, 16.8 Hz, 1 H), 2.70
(dd, J = 3.6, 16.8 Hz, 1 H), 2.01 (s, 3 H), 1.55 (s, 3 H), 1.47 (s, 3 H).
(4R)-5-Nitro-4-phenylhexan-2-one (4ba)5h
syn-Diastereomers
Colorless oil; yield: 36.4 mg (55%; 94% ee); [α]D25 –7.2 (c 0.36, CHCl3).
(4R)-5-Methyl-5-nitro-4-(4-tolyl)hexan-2-one (4bf)5f
Colorless oil; yield: 65.1 mg (87%; 95% ee); [α]D25 +30.1 (c 0.65, CHCl3).
HPLC: [Daciel Chiralpak AS-H, λ = 220 nm, eluent: i-PrOH–hexane
(1:99), flow rate: 0.9 mL/min]; tR = 30.4 min (major), 34.8 min (mi-
nor).
1H NMR (300 MHz, CDCl3): δ = 7.35–7.26 (m, 3 H), 7.21–7.18 (m, 2 H),
4.81–4.71 (m, 1 H), 3.75–3.67 (m, 1 H), 2.97 (dd, J = 9.6, 17.1 Hz, 1 H),
2.73 (dd, J = 4.5, 17.4 Hz, 1 H), 2.00 (s, 3 H), 1.31 (d, J = 6.6 Hz, 3 H).
HPLC: [Daciel Chiralpak AS-H, λ = 220 nm, eluent: EtOH–hexane
(1:99), flow rate: 0.9 mL/min]; tR = 27.5 min (major), 31.7 min (mi-
nor).
1H NMR (400 MHz, CDCl3): δ = 7.03–6.98 (m, 4 H), 3.82 (dd, J = 3.2,
10.8 Hz, 1 H), 3.00 (dd, J = 10.8, 17.2 Hz, 1 H), 2.60 (dd, J = 3.2, 17.2 Hz,
1 H), 2.22 (s, 3 H), 1.93 (s, 3 H), 1.46 (s, 3 H), 1.38 (s, 3 H).
anti-Diastereomers
Colorless oil; yield: 27.2 mg (41%; 84% ee); [α]D25 –6.8 (c 0.27, CHCl3).
HPLC: [Daciel Chiralpak AS-H, λ = 220 nm, eluent: i-PrOH–hexane
(1:99), flow rate: 0.9 mL/min]; tR = 30.9 min (minor), 35.8 min (ma-
jor).
1H NMR (300 MHz, CDCl3): δ = 7.34–7.27 (m, 3 H), 7.16–7.13 (m, 2 H),
4.92–4.83 (m, 1 H), 3.73 (q, J = 6.9, 13.8 Hz, 1 H), 3.05 (dd, J = 6.6, 17.7
Hz, 1 H), 2.90 (dd, J = 7.5, 17.4 Hz, 1 H), 2.12 (s, 3 H), 1.48 (d, J = 6.6 Hz,
3 H).
(4R)-4-(4-Methoxyphenyl)-5-methyl-5-nitrohexan-2-one (4bg)5f
25
Pale-yellow oil; yield: 67.7 mg (85%; 95% ee); [α]D +33.7 (c 0.67,
CHCl3).
HPLC: [Daciel Chiralpak AS-H, λ = 220 nm, eluent: i-PrOH–hexane
(10:90), flow rate: 0.9 mL/min]; tR = 15.5 min (minor), 18.2 min (ma-
jor).
1H NMR (400 MHz, CDCl3): δ = 7.03 (d, J = 8.8 Hz, 2 H), 6.74 (d, J = 8.8
Hz, 2 H), 3.80 (dd, J = 3.6, 10.8 Hz, 1 H), 3.69 (s, 3 H), 2.96 (dd, J = 10.8,
17.6 Hz, 1 H), 2.60 (dd, J = 3.6, 17.6 Hz, 1 H), 1.94 (s, 3 H), 1.46 (s, 3 H),
1.39 (s, 3 H).
(4R)-4-(4-Fluorophenyl)-5-methyl-5-nitrohexan-2-one (4bb)5f
Colorless oil; yield: 67.6 mg (89%; 92% ee); [α]D25 +29.2 (c 0.67, CHCl3).
HPLC: [Daciel Chiralpak AS-H, λ = 220 nm, eluent: i-PrOH–hexane
(10:90), flow rate: 0.9 mL/min]; tR = 13.6 min (major), 21.4 min (mi-
nor).
1H NMR (400 MHz, CDCl3): δ = 7.19–7.15 (m, 2 H), 7.02–6.97 (m, 2 H),
3.92 (dd, J = 3.2, 10.8 Hz, 1 H), 3.05 (dd, J = 10.8, 17.2 Hz, 1 H), 2.73
(dd, J = 3.2, 17.2 Hz, 1 H), 2.04 (s, 3 H), 1.55 (s, 3 H), 1.48 (s, 3 H).
(4S)-4-(1-Methyl-1-nitroethyl)nonan-2-one (4bh)4f
Colorless oil; yield: 56.4 mg (82%; 95% ee); [α]D25 +13.3 (c 0.56, CHCl3).
HPLC: [Daciel Chiralpak AD-H, λ = 220 nm, eluent: i-PrOH–hexane
(1:99), flow rate: 0.9 mL/min]; tR = 15.6 min (major), 16.8 min (mi-
nor).
1H NMR (400 MHz, CDCl3): δ = 2.72–2.66 (m, 1 H), 2.45 (dd, J = 4.4,
17.6 Hz, 1 H), 2.28 (dd, J = 6.0, 18.0 Hz, 1 H), 2.10 (s, 3 H), 1.45 (s, 3 H),
1.44 (s, 3 H), 1.34–1.26 (m, 1 H), 1.21–1.08 (m, 6 H), 1.04–0.98 (m, 1
H), 0.79 (t, J = 6.8 Hz, 3 H).
(4R)-4-(4-Chlorophenyl)-5-methyl-5-nitrohexan-2-one (4bc)5f
Colorless oil; yield: 72.1 mg (89%; 94% ee); [α]D25 +30.2 (c 0.72, CHCl3).
HPLC: [Daciel Chiralpak AS-H, λ = 220 nm, eluent: i-PrOH–hexane
(10:90), flow rate: 0.9 mL/min]; tR = 13.2 min (major), 16.3 min (mi-
nor).
1H NMR (400 MHz, CDCl3): δ = 7.28 (dd, J = 2.0, 7.2 Hz, 2 H), 7.12 (d,
J = 8.8 Hz, 2 H), 3.90 (dd, J = 3.6, 10.8 Hz, 1 H), 3.04 (dd, J = 10.8, 17.6
Hz, 1 H), 2.73 (dd, J = 3.6, 17.6 Hz, 1 H), 2.05 (s, 3 H), 1.54 (s, 3 H), 1.48
(s, 3 H).
(4S)-5-Methyl-5-nitro-4-(2-phenylethyl)hexan-2-one (4bi)5f
Colorless oil; yield: 69.6 mg (88%; 95% ee); [α]D25 +20.1 (c 0.69, CHCl3).
HPLC: [Daciel Chiralpak AS-H, λ = 220 nm, eluent: i-PrOH–hexane
(10:90), flow rate: 0.5 mL/min]; tR = 16.0 min (minor), 17.8 min (ma-
jor).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–J

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Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.27 (t, J = 7.2 Hz, 2 H), 7.18 (t, J = 7.2
Hz, 1 H), 7.12 (t, J = 7.2 Hz, 2 H), 2.87–2.82 (m, 1 H), 2.62–2.51 (m, 3
H), 2.42 (dd, J = 6.4, 18.0 Hz, 1 H), 2.16 (s, 3 H), 1.77–1.68 (m, 1 H),
1.52 (s, 3 H), 1.50 (s, 3 H), 1.45–1.37 (m, 1 H).
γ-Aminobutyrates 6; General Procedure
NaBH4 (3.6 mmol) was added in a portionwise manner to a solution
of compound 5 (0.3 mmol) and NiCl2·6 H2O (0.3 mmol) in EtOH (3 mL)
at 0 °C, and the mixture was then stirred at 0 °C until the reaction was
complete (TLC). The reaction was quenched with sat. aq NH4Cl (3 mL)
and the mixture was extracted with CH2Cl2 (3 × 5 mL). The organic
layers were combined, dried (Na2SO4), filtered, and concentrated un-
der reduced pressure. The residue was purified by column chroma-
tography.
(4R)-4-(1-Nitrocyclopentyl)-4-phenylbutan-2-one (4bj)5h
Colorless oil; yield: 72.7 mg (93%; 92% ee); [α]D25 +3.5 (c 0.72, CHCl3).
HPLC: [Daciel Chiralpak AS-H, λ = 220 nm, eluent: i-PrOH–hexane
(10:90), flow rate: 0.9 mL/min]; tR = 10.0 min (major), 14.0 min (mi-
nor).
1H NMR (400 MHz, CDCl3): δ = 7.29–7.23 (m, 3 H), 7.15–7.13 (m, 2 H),
3.88 (dd, J = 3.6, 10.0 Hz, 1 H), 3.13 (dd, J = 10.0, 17.2 Hz, 1 H), 2.90
(dd, J = 4.0, 17.2 Hz, 1 H), 2.57–2.44 (m, 2 H), 2.01 (s, 3 H), 1.87–1.78
(m, 2 H), 1.68–1.56 (m, 4 H).
Isopropyl (3R)-4-Amino-3-phenylbutanoate (6a)19
Pale-yellow oil; yield: 58.4 mg (88%).
1H NMR (300 MHz, CDCl3): δ = 7.31–7.26 (m, 2 H), 7.22–7.17 (m, 3 H),
4.92–4.84 (m, 1 H), 3.17–3.07 (m, 1 H), 2.96–2.81 (m, 2 H), 2.68 (dd,
J = 7.2, 15.0 Hz, 1 H), 2.55 (dd, J = 8.1, 15.0 Hz, 1 H), 1.91 (s, 2 H), 1.11
(d, J = 6.3 Hz, 3 H), 1.05 (d, J = 6.3 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 171.9, 141.9, 128.8, 128.0, 127.1, 67.9,
47.6, 45.9, 39.3, 21.9 (d).
γ-Nitro Esters 5; General Procedure
m-CPBA (0.9 mmol) was added to a solution of γ-nitro ketone 4 (0.3
mmol) and TFA (0.3 mmol) in CH2Cl2 (3 mL), and the mixture was re-
fluxed until the reaction was complete (TLC). The solvent was re-
moved under reduced pressure and the residue was purified by col-
umn chromatography.
Isopropyl (3R)-4-Amino-3-(4-chlorophenyl)butanoate (6b)20
Pale-yellow oil; yield: 69.1 mg (90%).
1H NMR (300 MHz, CDCl3): δ = 7.25 (d, J = 8.1 Hz, 2 H), 7.12 (d, J = 6.6
Hz, 2 H), 4.91–4.82 (m, 1 H), 3.15–3.05 (m, 1 H), 2.93–2.78 (m, 2 H),
2.64 (dd, J = 6.9, 15.0 Hz, 1 H), 2.47 (dd, J = 8.1, 15.0 Hz, 1 H), 1.90 (s, 2
H), 1.10 (d, J = 6.3 Hz, 3 H), 1.05 (d, J = 6.3 Hz, 3 H).
Isopropyl (3R)-4-Nitro-3-phenylbutanoate (5a)
25
Pale-yellow oil; yield: 70.1 mg (93%; 98% ee); [α]D +21.8 (c 0.56,
CHCl3).
13C NMR (75 MHz, CDCl3): δ = 171.7, 140.5, 132.8, 129.4, 129.0, 68.0,
47.5, 45.2, 39.1, 21.9 (d).
HPLC: [Daciel Chiralpak AS-H, λ = 220 nm, eluent: i-PrOH–hexane
(10:90), flow rate: 0.9 mL/min]; tR = 14.6 min (major), 19.4 min (mi-
nor).
IR (KBr, film): 2981, 2935, 1720, 1550, 1375, 1107, 964, 763, 700, 530
γ-Aminobutyric Acids; General Procedure
cm–1
.
γ-Amino butyrate 6 (0.25 mmol) was added to 6 M aq HCl (5 mL), and
the suspension was heated at 100 °C until the reaction was complete
(TLC). The mixture was cooled to r.t., diluted with deionized H2O (10
mL), and washed with Et2O (2 × 10 mL). Finally, the aqueous layer was
concentrated in vacuo.
1H NMR (300 MHz, CDCl3): δ = 7.32–7.18 (m, 5 H), 4.94–4.85 (m, 1 H),
4.72–4.55 (m, 2 H), 3.99–3.89 (m, 1 H), 2.71–2.63 (m, 2 H), 1.10 (t,
J = 6.3 Hz, 6 H).
13C NMR (75 MHz, CDCl3): δ = 170.3, 138.5, 129.2, 128.2, 127.6, 79.7,
68.6, 40.5, 38.2, 21.9.
(R)-Phenibut Hydrochloride [(3R)-4-Amino-3-phenylbutanoic
HRMS (EI): m/z calcd for C13H17NO4: 251.1158; found: 251.1160
Acid Hydrochloride]16f
White solid; yield: 51.4 mg (95%).
1H NMR (300 MHz, D2O): δ = 7.31–7.16 (m, 5 H), 3.29–3.17 (m, 2 H),
3.13–3.02 (m, 1 H), 2.74–2.53 (m, 2 H).
13C NMR (75 MHz, D2O): δ = 175.6, 138.5, 129.5, 128.4, 128.0, 43.9,
Isopropyl (3R)-3-(4-Chlorophenyl)-4-nitrobutanoate (5b)
Pale-yellow oil; yield: 78.8 mg (92%; 98% ee); [α]D25 +28.1 (c 0.55, CH-
Cl3).
HPLC: [Daciel Chiralcel OD-H, λ = 220 nm, eluent: i-PrOH–hexane
(10:90), flow rate: 0.9 mL/min]; tR = 15.9 min (major), 20.9 min (mi-
nor).
40.0, 38.4.
(R)-Baclofen Hydrochloride [(3R)-4-Amino-3-(4-chlorophenyl)bu-
IR (KBr, film): 2981, 2935, 1728, 1556, 1494, 1377, 1107, 833, 542
tanoic Acid Hydrochloride]17o
cm–1
.
Pale-yellow solid; yield: 58.3 mg (93%).
1H NMR (300 MHz, D2O): δ = 7.29–7.23 (m, 2 H), 7.18–7.12 (m, 2 H),
3.29–3.16 (m, 2 H), 3.10–3.01 (m, 1 H), 2.72–2.51 (m, 2 H).
13C NMR (75 MHz, D2O): δ = 175.5, 137.1, 133.5, 129.5, 129.4, 43.8,
1H NMR (300 MHz, CDCl3): δ = 7.26 (d, J = 9.6 Hz, 2 H), 7.13 (d, J = 8.1
Hz, 2 H), 4.93–4.85 (m, 1 H), 4.66 (dd, J = 6.6, 12.9 Hz, 1 H), 4.55 (dd,
J = 8.1, 12.3 Hz, 1 H), 3.97–3.86 (m, 1 H), 2.68–2.63 (m, 2 H), 1.10 (t,
J = 6.3 Hz, 6 H).
39.6, 38.4.
13C NMR (75 MHz, CDCl3): δ = 170.0, 137.0, 134.0, 129.3, 129.0, 79.4,
68.8, 39.9, 38.0, 21.8.
HRMS (EI): m/z calcd for C13H16ClNO4: 285.0768; found: 285.0767.
Acknowledgment
We are grateful for financial support from the National Natural Sci-
ence Foundation of China (Nos. 21242007 and 21102043) and the
Fundamental Research Funds for the Central Universities.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–J

I
X.-T. Guo et al.
Paper
Synthesis
Supporting Information
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Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380203.
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(13) With catalyst 1a; 4aa: 43% yield, 97% ee; 4ag: 43% yield, 97% ee;
4ap: 18% yield, 80% ee; 4aq: 51% yield, 95% ee. With catalyst 1g;
4aa: 40% yield, 97% ee; 4ag: 41% yield, 97% ee; 4ap: 18% yield,
79% ee; 4aq: 38% yield, 96% ee.
(14) For the comparative pharmacological activities of the two enan-
tiomers of baclofen, see: (a) Olpe, H.-R.; Demiéville, H.; Baltzer,
V.; Bencze, W. L.; Koella, W. P.; Wolf, P.; Haas, H. L. Eur. J. Phar-
macol. 1978, 52, 133. (b) Paredes, R.; Agmo, A. Psychopharma-
cology (Heidelberg, Ger.) 1989, 97, 358. (c) Fromm, G. H.;
Shibuya, T.; Nakata, M.; Terrence, C. F. Neuropharmacology
1990, 29, 249.
(18) (a) Drake, N. L.; Allen, P. Jr. Org. Synth. Coll. Vol. I; Wiley: London,
1941, 77. (b) Kohler, E. P.; Chadwell, H. M. Org. Synth. Coll. Vol. I;
Wiley: London, 1941, 78.
(19) Veinberg, G.; Vorona, M.; Lebedevs, A.; Chernobrovijs, A.;
Kalvinsh, I. WO 2007096314, 2007.
(20) Leisen, C.; Langguth, P.; Herbert, B.; Dressler, C.; Koggel, A.;
Spahn-Langguth, H. Pharm. Res. 2003, 20, 772.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–J