Biscinchona alkaloids as highly efficient bifunctional organocatalysts for the asymmetric conjugate addition of malonates to nitroalkenes at ambient temperature

Article abstract of DOI:10.1016/j.tet.2011.08.070

The novel bifunctional bisalkaloids have been developed as highly efficient catalysts for the asymmetric conjugate addition of 1,3-dicarbonyl compounds to nitroalkenes with low catalyst loading (1 mol %) at ambient temperature, providing the products with

Full text of DOI:10.1016/j.tet.2011.08.070

Tetrahedron 67 (2011) 10186e10194
Contents lists available at SciVerse ScienceDirect
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journal homepage: www.elsevier.com/locate/tet
Biscinchona alkaloids as highly efficient bifunctional organocatalysts for the
asymmetric conjugate addition of malonates to nitroalkenes at ambient
temperature
,
a,
Fei Li a, Ying-Zi Li a, Zhen-Shan Jia a, Ming-Hua Xu b, Ping Tian a , Guo-Qiang Lin
*
*
a CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
b Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 May 2011
Received in revised form 23 August 2011
Accepted 23 August 2011
Available online 27 August 2011
The novel bifunctional bisalkaloids have been developed as highly efficient catalysts for the asymmetric
conjugate addition of 1,3-dicarbonyl compounds to nitroalkenes with low catalyst loading (1 mol %) at
ambient temperature, providing the products with excellent enantioselectivities (up to 97% ee).
Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
Dedicated to Professor Gilbert Stork on the
occasion of his 90th birthday on December
31, 2011
Keywords:
Bifinctional
Biscinchona alkaloids
Nitroalkenes
Conjugate addition
Baclofen
1. Introduction
reaction,10 formal [3þ2]cycloaddition reaction,11 Kornblum DeLaM-
are rearrangement reaction,12 and -amination reaction.13
a
Readily available and inexpensive cinchona alkaloids with their
pseudoenantiomeric forms, such as quinine and quinidine or cin-
chonine and cinchonidine, are among the most privileged chiral
catalysts orligandsintheareaofasymmetriccatalysis.1,2 Forinstance,
the demethylated C60eOH cinchona alkaloids along with their C9-O
substituted derivatives (Q1aec and QD1aec), in which C60eOH
group serves as an effective H-bond donor, while the tertiary qui-
nuclidine nitrogen acts as a powerful Lewis base, were first suc-
cessfully used as catalysts for the enantioselective conjugate addition
of malonates to nitroalkenes (Fig.1).5c Indeed, to date these cinchona
Among these reactions, modification of cinchona alkaloids’
0
C9eOH appears to hinder free rotation of C8eC9 and C4 eC9
s-
bonds and favor only a narrow range of the conformational space of
the molecules, which could be more adaptable toward structural
variation for optimization of catalyst activity and selectivity.
Lewis Base
N
N
H-Bond donor
H-Bond donor
O
O
H
8
R
8 H
alkaloids derivatives including
b-isocupreidine (b-ICD, Q2), have
R
9
9
4'
4'
HO 6'
OH
6'
been developed and already shown outstanding bifunctionally cat-
Conformation
Control
alytic abilities in numerous reactions, such as MoritaeBayliseHill-
N
N
man reaction,3,4 conjugate additionto nitroalkenes,5
a,b-unsaturated
Q1
QD1
6'-deMe-Quinine (
)
6'-deMe-Quinidine(
)
N
aldehydes,6a ketones,6b cyanides,6c and sulfones,6d Henry reaction,7
6'-Hydroxycinchonine
6'-Hydroxycinchonine
O
Mannich reaction,8 allylic nucleophilic substitution,9 DielseAlder
H
QD1a: R = H;
QD1b: R = Bn;
Q1a: R = H;
OH
Q1b: R = Bn;
QD1c
Q1c
: R =
: R =
N
(PHN)
(PHN)
β-ICD, Q2
* Corresponding authors. Tel.: þ86 21 54925169; fax: þ86 21 64166263; e-mail
addresses: tianping@sioc.ac.cn (P. Tian), lingq@mail.sioc.ac.cn (G.-Q. Lin).
Fig. 1. Active sites in bifunctional cinchona alkaloid catalysts.
0040-4020/$ e see front matter Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.08.070

F. Li et al. / Tetrahedron 67 (2011) 10186e10194
10187
Furthermore, extensive studies focused on skeleton modification of
cinchona alkaloids in Sharpless AD reaction had demonstrated that
second generation dimeric ligands, such as (DHQ)2PHAL, which
possessed an enzyme-like binding pocket14 showed superior ac-
tivity and selectivity than those monomers bearing C9eO sub-
stituents Q3 in most cases. Inspired by the successful achievement
of dimeric cinchona alkaloids in Sharpless AD reaction, we hope to
design a new type of biscinchona alkaloid, which could be utilized
as an efficient catalyst in other asymmetric field. Herein, we dis-
close the first synthesis of bis(demethylated-alkaloids) organo-
catalysts Q4 and QD4, as well as the application in the addition of
malonates to nitroalkenes (Scheme 1).
(both quinuclidine rings are opposite to each other with respect to
the PHAL ring) is adopted in the crystal lattice. The structure
showed that both quinuclidine rings of Q4 are hydrogen bonded to
methanol molecules but substructures exposed that N2 hydrogen
bonded to methanol O10 toward its intramolecular bystander
ꢀ
quinolyl ring at 2.056 A and N6 hydrogen bonded to methanol O11
toward intermolecular bystander quinolyl ring of another Q4 at
ꢀ
1.984 A. The packing forces are mainly due to the intermolecular H-
bond between quinolyl ring and phenolic hydroxy group at the
ꢀ
length of 1.893 A (Fig. 2). In conclusion, the crystallographic data
not only proves that each independent demethylated dihy-
droquinine part can be used as a chiral catalytic center, but also
reveals its bystander quinolyl ring and the phthalazine plane ring
could provide steric blocking for other operative alkaloid moiety
and vice versa (identify with the binding pocket).
N
Et
Et
OMe
N
N
N
N
OR
O
O
2.2. Asymmetric conjugate addition to nitroalkenes
in AD reaction
MeO
N
MeO
Et
The Michael addition of malonates to nitroalkenes was selected
as a model reaction. In this system, high enantioselectivity has been
achieved catalyzed by cinchona alkaloids Q1a at low temperature
by Deng et al.5 Good results have also been achieved with chiral
transition metal complexes17 or bifunctional organic catalysts de-
rived from chiral thioureas,18 guanidines,19 and amino-
benzimidazoles.20 However, there is still room for improvement in
terms of both reaction mildness and lower catalyst loading.
Initially, addition of dimethyl malonate 3a to nitroalkene 2a
catalyzed by 5 mol % of Q4 at ambient temperature (ca. 20 ꢀC) was
investigated in THF. Gratifyingly, the adduct 4a was obtained with
almost quantitative yield and excellent enantioselectivity (94% ee)
(entry 1, Table 1). Decrease of the reaction temperature resulted in
little enantioselectivity improvement but much longer reaction
time (entries 2 and 3 vs 1). It indicates that the selectivity of the
catalyst Q4 was less sensitive to the temperature than that of Q1a
described in the literature (entries 4 and 5). Better results were
achieved with dimethyl rather than diethyl malonate 3b or diiso-
propyl malonate 3c (entries 6 and 7 vs 1). Then, the loading of
catalyst could be reduced to 1 mol % without compromising the
enatioselectivity (entries 8 and 9). The studies using Q1a and Q5a
that afforded the same results demonstrated that C10eC11 double
or single bond is less effective of the enantioselectivity in this re-
action (entries 10 and 11). Screening with 1 mol % amount catalysts
uncovered that among the catalysts of O9 substituents, Q4 gave the
best catalyst performance in terms of the reactivity and selectivity
(entries 9e13), reaching up to 99% yield and 94% ee at room tem-
perature. Finally THF was the best choice of solvent. (Entries 14e17
vs 9.) Thus the best reaction conditions were acquired using di-
methyl malonate 3a as substrate catalyzed by 1 mol % of catalyst Q4
in THF at room temperature.
Having established the optimized reaction conditions, we then
turned our attention to substrate generality. A variety of aromatic
and aliphatic trans-nitroalkenes were evaluated under the condi-
tions. All aromatic nitroalkenes with either electron-donating or
electron-withdrawing groups on aromatic rings can proceed
smoothly to give the corresponding adducts 4 or 5 with excellent
yields and enantioselectivities (Table 2, entries 1e10). High enan-
tioselectivities and yields were also observed with aliphatic nitro-
alkenes (entries 11e14). All of the results prove that the biscinchona
alkaloid organocatalysts Q4 or QD4 exhibit good to excellent
compatibility with the various nitroalkene substrates.
In the course of substrate investigation, we found that catalyst
Q4 had not so much apparent advantage over Q1a, especially when
a hydrogen-affinity group was in the para position of the aryl ring
(entry 2 and 3 Table 3). It was supposed that two H-bonds formed
between catalyst and the nitroalkene substrate (two phenolic hy-
droxides and the NO2 and H-affinity group, such as MeO, F, NO2 in
N
N
(DHQ)2PHAL
O
Q3c: R =
Q3a: R =
(CLB)
Cl
N
Q3b: R = PHN
(MEQ)
N
Steric
group
Et
Et
OH
N
N
Catalytic
center
this work
OR
O
Catalytic
center
Linker
O
N
HO
HO
C2-Symmetry
Et
N
N
Q1
deMeDHQ-
N
N
Et
Et
OH
OH
N
N
N
N
N
N
O
O
O
O
N
N
HO
HO
Et
Et
N
N
Q4
QD4
(deMeDHQD)2PHAL-
(deMeDHQ)2PHAL-
Scheme 1. Concept and design of bisalkaloid catalysts Q4 and QD4.
2. Results and discussion
2.1. Preparation of bisalkaloid catalysts Q4 and QD4
Our investigations began with the preparation of biscinchona
alkaloid catalyst (deMeDHQ)2PHALeQ4. Direct demethylation of
(DHQ)2PHAL with strong acid15 or NaSEt5c afforded complicated
products and no bisphenolic product Q4 was obtained. Due to the
high sensitivity of phthalazinyl ether to strong acid or nucleophilic
reagent, demethylation had to be performed on a synthetic pre-
cursor. Treated with HBr (aq, 40%) dihydroquinine was successfully
converted to the demethylated product Q5a, and phenolic hydroxy
group was selectively protected by triphenylmethyl group to give
Q6 by using phase transfer reaction. Through nucleophilic sub-
stitution, two Q6 molecules coupled with dichlorophthalazine 1
(PHAL), and the product Q7 was deprotected under acidic condition
giving the biscinchona alkaloid catalyst (deMeDHQ)2PHALeQ4 in
an overall 54% yield16 (Scheme 2). Bisalkaloid catalyst QD4 was
obtained from dihydroquinidine (DHQD) via the same procedures.
To gain insight into the steric nature of these novel catalysts,
single-crystal X-ray diffraction of crystals of Q4 obtained in meth-
anol was conducted. X-ray diffraction analysis indicated that
transoid conformation of di[demethyl(dihydroquinine)] moieties

10188
F. Li et al. / Tetrahedron 67 (2011) 10186e10194
Et
Et
Et
N
N
N
OH
OH
OH
b) Ph3CCl, NaOH
a) HBr(40%)
Reflux
90%
MeO
TrtO
Bu4NBr, DME/H2O
95%
HO
N
N
N
Q5a
Q6
DHQ (Dihydroquinine)
N
Et
N
N
OTrt
N
N
N
c) NaH,THF
Reflux
Cl
Cl
O
O
N
74%
TrtO
Et
N
1
Q7
N
Et
OH
N
N
N
d) HCO2H
O
O
Et2O, RT
85%
N
HO
Et
N
Q4
(deMeDHQ)2PHAL-
Scheme 2. Preparation of bisalkaloid catalyst Q4.
entries 2e4) resulted in the reduced catalyzing effect. Therefore,
a mono-protected catalyst Q8, which will never form a second H-
bond with substrate was synthesized21 and evaluated in the re-
action. The higher selectivity catalyzed by Q8 testified the suppo-
sition to some extent obviously when substrates 2h and 2o were
used (entry 3 and 4 Table 3). On the other hand, the distances be-
ꢀ
tween the two phenolic O atoms of Q4 are 6.040 A (O1eO4) and
5.570 A (O5eO8) in the lattice,22 which also suggested the possible
ꢀ
existence of double H-bond interaction to the substrates (Fig. 2).
2.3. Asymmetric synthesis of optical (R)-(L)-baclofen
The chiral adducts 4 and 5 can be easily transformed to the
chiral
b-substituted g-lactams, which are very useful building
blocks for assembling some bioactive compounds.5,18e21 Herein,
the synthetic application of this methodology is demonstrated by
a four-step synthesis of a selective GABAB receptor agonist, (R)-
baclofen hydrochloride.23
After a single recrystallization, the optically pure adduct 5b was
obtained with >99% ee and further converted to (R)-4-(4-
chlorophenyl)-2-pyrrolidinone 7 in four steps with overall 72%
yield, which was easily hydrolyzed to afford optical pure (R)-
baclofen hydrochloride 8 (Scheme 3).
3. Summary
In summary, the novel powerful chiral bifunctional bisalkaloid
organocatalysts Q4 and QD4 have been developed and applied to
the conjugate addition of dimethyl malonate to nitroalkenes. These
addition reactions proceed with low catalyst loading (1 mol %) at
ambient temperature with excellent enantioselectivities. These
addition products are important intermediates for the syntheses of
chiral 4-substituted pyrrolidinones and optically pure (R)-baclofen
was prepared as a demonstration. Further studies and extension of
these two catalysts are currently underway.
Fig. 2. X-ray crystal structure of (deMeDHQ)2PHALeQ4.

F. Li et al. / Tetrahedron 67 (2011) 10186e10194
10189
Table 1
Asymmetric conjugate addition of malonates to nitroalkene 2aa,b
RO2C
CO2R
NO2
NO2
Cat. (x mol%)
RO2C
R=Me
CO2R
Solvent (1.0 M)
3a
3b
R=Et
R=i-Pr 3c
2a
4
10
11
N
11
N
N
Et
OH
OR
N
OR
N
N
O
HO
O
HO
N
HO
Et
N
N
Q1a
: R = H;
: R =
N
Q5a
: R= H
: R = Bn;
Q4
(deMeDHQ)2PHAL-
Q1c
Q5b
(PHN)
Entry
T (ꢀC)
11 (mol %)
Cat
3
Sol
Time (h)
Yieldc (%)
eed (%)
1
2
3
4
5
6
7
8
20
10
0
5
5
5
10
10
5
5
3
1
2
2
2
2
1
1
1
1
Q4
Q4
Q4
Q1a
Q1a
Q4
Q4
Q4
Q4
Q1a
Q5a
Q5b
Q1c
Q4
Q4
Q4
Q4
3a
3a
3a
3a
3a
3b
3c
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
DCM
DMF
Dioxane
DCE
6
12
36
2
36
18
72
10
20
6
99
99
99
99
97
99
90
99
99
98
99
98
97
96
73
98
75
94
95
96
89
96
63
57
94
94
89
89
90
92
94
57
94
91
20
ꢃ20
20
20
20
20
20
20
20
20
20
20
20
20
9
10
11
12
13
14
15
16
17
6
12
60
26
72
30
72
a
Reactions were carried out at different temperature with 0.2 mL of solvent using 0.2 mmol of 2a (1.0 equiv), 0.6 mmol of 3 (3.0 equiv), and catalyst, unless otherwise stated.
b
c
The absolute configuration of 4a was determined by comparison of the specific rotation of the corresponding literature.17a
Isolated yield.
Determined by HPLC analysis using a chiral column.
d
4. Experimental
to give a brown solid (34.7 g, 90% yield). 1H NMR (300 MHz, CD3OD)
d
8.70 (d, J¼4.6 Hz, 1H), 7.98 (d, J¼9.1 Hz, 1H), 7.78 (d, J¼4.5 Hz, 1H),
4.1. General methods
7.52e7.30 (m, 2H), 6.02 (s, 1H), 4.40e4.15 (m, 1H), 3.76e3.51 (m,
2H), 3.36e3.17 (m, 1H), 3.08e3.01 (m, 1H), 2.41e1.79 (m, 5H),
1.65e1.49 (m, 1H), 1.47e1.23 (m, 2H), 0.89 (t, J¼7.4 Hz, 3H); ESI-MS
All solvents were dried before use following the standard pro-
cedures. Unless otherwise indicated, all starting materials were
obtained from commercial suppliers and were used without further
purification. The 1H and 13C NMR spectra were recorded on 300 or
400 MHz spectrometers in the indicated solvents. Chemical shifts
(m/z): 313.2 (MþHþ); ½a D27
ꢃ149.4 (c 1.23, EtOH).
ꢂ
60-Hydroxy dihydroqunidine QD5a3e was obtained as a brown
solid (32.5 g, 85% yield). 1H NMR (400 MHz, DMSO-d6)
d 8.69 (d,
J¼4.4 Hz,1H), 7.92 (d, J¼9.7 Hz,1H), 7.57 (d, J¼4.4 Hz,1H), 7.45e7.27
(m, 2H), 6.41 (d, J¼3.5 Hz, 1H), 5.86 (br s, 1H), 3.76e3.60 (m, 1H),
3.53e3.12 (m, 4H), 2.32e2.14 (m, 1H), 1.94e1.65 (m, 4H), 1.62e1.40
are reported in
d (ppm) referenced to an internal TMS standard for
1H NMR and CDCl3
(d
¼77.05 ppm) for 13C NMR. Optical rotations
were measured on a JASCO P-1030 polarimeter.
(m, 2H), 1.25e1.06 (m, 1H), 0.89 (t, J¼7.3 Hz, 3H). ½a D27
þ168.9 (c
ꢂ
1.05, EtOH); ESI-MS (m/z): 313.5 (MþHþ).
4.2. Preparation of catalysts
4.2.2. 60-TrtO-dihydroquinine Q6. To the solution of NaOH (3.84 g,
96 mmol) in water (50 mL) were added Q5 (10 g, 32 mmol) and
Bu4NBr (103 mg, 0.32 mmol). The resulting mixture was stirred at
room temperature for 15 min. Then solution of Ph3CCl (9.35 g,
33.5 mmol) in CH2Cl2 (50 mL) was added dropwise in 30 min. The
reaction mixture was stirred for 2 h and the organic phase was
separated. Another solution of Ph3CCl (0.94 g, 3.4 mmol) in CH2Cl2
(20 mL) was added to the aqueous phase. The reaction mixture was
stirred for 2 h and the organic phase was separated. The combined
organic phase was washed with solution of NaOH (aq, 10%) and
brine, dried over Na2SO4, and concentrated in vacuo. The residue
4.2.1. 60-Hydroxy dihydroquinine Q5a. The solution of dihyr-
oquinine (40 g, 12.3 mmol) in 500 mL of HBr (aq, 40%) was stirred
and refluxed until a TLC analysis showed the starting material was
completely consumed (12e24 h). The solution was removed about
1/3 volume under reduced pressure when the reaction mixture was
cooled down to room temperature, and then mixed with satd NH3
(aq, 25e27%). The pH value of the solution was adjusted to be
around 7. The resulting mixture was extracted with solution of
CH2Cl2 and MeOH (10/1, 3ꢁ100 mL). The organic phase was washed
with water (50 mL), dried over Na2SO4, and concentrated in vacuo

10190
F. Li et al. / Tetrahedron 67 (2011) 10186e10194
702; ½a 2D0
ꢂ
ꢃ197.9 (c 1.23, CHCl3); ESI-MS (m/z): 555.4 (MþHþ);
Table 2
Asymmetric conjugate addition of 3a to nitroalkenesa
HRMS (ESI-MS) for C38H39N2O2(MþHþ): calcd 555.3005, found
555.3006.
3a
MeO2C
CO2Me
NO2
4a to n for Q4
MeO2C
CO2Me
NO2
Q4 or QD4 (1 mol%)
THF(1.0M),RT (20oC)
NO2
60-TrtO-dihydroquinidine QD6 was obtained as a yellowish foam
R
or
R
R
(91% yield). 1H NMR (400 MHz, CDCl3)
d
8.46 (d, J¼4.5 Hz, 1H), 7.77
(d, J¼9.2 Hz, 1H), 7.50 (d, J¼7.6 Hz, 6H), 7.34e7.05 (m, 12H), 4.94 (d,
2
5a to n for QD4
J¼6.5 Hz, 1H), 2.85e2.39 (m, 5H), 1.68e1.14 (m, 7H), 1.10e0.93 (m,
1H), 0.81 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 154.1, 147.9,
Entry
Nitroalkenes
R
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
Phe
24 (24)
18 (24)
18 (24)
18 (24)
18 (24)
36 (36)
48 (48)
18 (24)
18 (24)
36 (36)
60 (72)
60
97 (98)d
97 (98)d
>99 (98)d
97 (99)d
97 (97)d
97 (97)d
99 (98)d
>99 (99)d
94 (ꢃ92)d
95 (ꢃ92)d
96 (ꢃ93)d
94 (ꢃ92)d
95 (ꢃ92)d
93 (ꢃ93)d
94 (ꢃ91)d
90 (ꢃ90)d
147.4,144.3,143.8,130.6,128.9,127.9,127.4,126.2,125.0,119.0,111.6,
90.8, 71.8, 59.6, 50.9, 49.8, 37.4, 27.0, 26.1, 25.1, 22.7, 12.0; FT-IR (KBr,
4-ClePhe
2-ClePhe
4-BrePhe
2-BrePhe
4-MeePhe
4-MeOePhe
4-FePhe
cmꢃ1
)
n
2930, 2869,1616, 1505, 1448,1217, 1186, 703; ½a D27
þ171.7 (c
ꢂ
1.06, CHCl3); ESI-MS (m/z): 555.3 (MþHþ); HRMS (ESI-MS) for
C38H39N2O2(MþHþ): calcd 555.3004, found 555.3006.
4.2.3. (60-TrtO-dihydroquinine)2PHAL Q7. Under N2 atmosphere, to
a solution of dried compound Q6 (16.6 g, 30 mmol) in THF (60 mL,
freshly distilled in the presence of Na) was added NaH (1.44 g, 60%
oil dispersion, 1.2 equiv) in small portions. The resulting mixture
9
1-Naphthyle
2-Furyle
98(>99)d
98 (96)d
90 (91)d
96 (ꢃ93)d
97 (ꢃ95)d
90 (ꢃ84)d
89
10
11f
12g
13f
14
PhCH]CHee
Cyclohexyl-
iso-Butyl
92
79
83
72
60
89
86
was stirred at room temperature for
2
h. Then 1,4-
PhCH2CH2e
dichlorophthalazine (2.98 g, 15 mmol) was added in three por-
tions under N2 atmosphere at 0 ꢀC. The reaction mixture was then
warmed and refluxed. When the reaction was completed, water
(5 mL) was added to quench. The mixture was extracted with EtOAc
and washed with brine. The organic phase was dried over Na2SO4
and concentrated in vacuo. The residue was purified by flash
chromatography (MeOH/CH2Cl2¼1/50 to 1/25 to 1/15) to give
a yellowish foam (13.7 g, 74% yield). 1H NMR (400 MHz, CDCl3)
a
Unless noted, reactions were carried out at room temperature with 0.2 mL of
THF using 0.2 mmol of 2 (1.0 equiv), 0.6 mmol of 3a (3.0 equiv), and catalyst Q4 or
QD4 (1 mol %).
b
Isolated yield.
Determined by HPLC analysis using a chiral column.
Results in parentheses were obtained with (deMeDHQD)2PHALeQD4.
trans-Double bond.
The catalyst Q4 or QD4 was used with 3 mol %.
The catalyst Q4 was used with 5 mol %.
c
d
e
f
g
d
8.56 (d, J¼4.5 Hz, 2H), 8.25 (dd, J¼6.0, 3.3 Hz, 2H), 7.86 (dd, J¼5.9,
3.3 Hz, 2H), 7.73 (d, J¼9.2 Hz, 2H), 7.56e7.39 (m, 14H), 7.31 (d,
J¼4.4 Hz, 2H), 7.20e7.06 (m, 14H), 6.98 (t, J¼7.1 Hz, 6H), 6.45 (d,
J¼5.2 Hz, 2H), 3.17e2.68 (m, 6H), 2.50e2.34 (m, 2H), 2.11e1.87 (m,
2H), 1.79e1.53 (m, 8H), 1.47e1.11(m, 8H), 0.84 (t, J¼7.2 Hz, 6H); 13C
Table 3
Asymmetric conjugate addition of 3a to nitroalkenesa
MeO2C
CO2Me
NO2
( E)
NO2
MeO2C
CO2Me
3a
NMR (100 MHz, CDCl3)
d 156.2, 154.6, 148.0, 145.2, 144.9, 143.9,
R1
132.2, 130.7, 129.1, 129.1, 128.0, 127.5, 126.4, 125.5, 123.0, 122.6,
113.0, 91.4, 59.9, 58.8, 42.9, 37.7, 29.0, 27.9, 25.9, 23.5, 12.4; FT-IR
THF, cat (1 mol%), RT
R1
(KBr, cmꢃ1
) n 2927, 2861, 1616, 1504, 1448, 1354, 1186, 701; ESI-
4
2
MS (m/z): 1274.7 (MþKþ), 1257.8 (MþNaþ), 1235.8 (MþHþ), 618.7
N
(Mþ2Hþ); ½a 2D7
þ108.1 (c 1.02, CHCl3); ESI-MS (m/z): 1235.7
ꢂ
(MþHþ),
619.3
(Mþ2Hþ);
HRMS
(ESI-MS)
for
Et
OH
OR2
N
C84H79N6O4(MþHþ):calcd 1235.6157, found 1235.6150.
N
N
N
(60-TrtO-dihydroquinidine)2PHAL QD7 was obtained as a yellow-
O
O
OH
N
ish foam (63% yield). 1H NMR (400 MHz, CDCl3)
d
8.59 (d, J¼4.4 Hz,
HO
Et
2 H), 8.24 (dd, J¼5.1, 2.9 Hz, 2H), 7.83 (dd, J¼6.0, 3.2 Hz, 2H), 7.72 (d,
J¼9.2 Hz, 2H), 7.58e7.31 (m, 16H), 7.22e6.98 (m, 20H), 6.46 (d,
J¼6.3 Hz, 2H), 3.13e2.92 (m, 2H), 2.76e2.31 (m, 8H), 1.85e1.70 (m,
2H), 1.38 (m, 14H), 0.80 (t, J¼7.0 Hz, 6H); 13C NMR (100 MHz, CDCl3)
N
N
Q1a
Q4 R2 = H;
Q8
R
2 = Me
d
156.3, 154.3, 147.9, 144.9, 143.8, 132.0, 130.5, 129.0, 127.9, 127.4,
Entry
Nitroalkenes
R1
eeb (%) (Q1a)
eeb (%) (Q4)
eeb (%) (Q8)
126.2, 125.3, 122.9, 122.4,113.3, 91.2, 59.6, 50.6, 49.9, 45.9, 37.5, 27.2,
1
2
3
4
2a
2g
2h
2o
H
89
93
91
76
94
94
90
81
93
94
93
89
26.4, 25.3, 23.5, 11.9; FT-IR (KBr, cmꢃ1
) n 3445, 2931, 2870, 1616,
1504, 1387, 1355, 702; ½a D27
ꢃ24.4 (c 1.06, CHCl3); ESI-MS (m/z):
ꢂ
4-MeO
4-F
4-NO2
1235.8 (MþHþ), 618.7 (Mþ2Hþ); HRMS (ESI-MS) for
C84H79N6O4(MþHþ): calcd 1235.6157, found 1235.6136.
a
Unless noted, reactions were carried out at room temperature with 0.2 mL of
THF using 0.2 mmol of 2 (1.0 equiv), 0.6 mmol of 3a (3.0 equiv), and catalyst Q1a, Q4
or Q8 (1 mol %).
4.2.4. (deMeDHQ)2PHAL Q4. A mixture of compound Q7 (3.7 g,
3 mmol), Et2O (15 mL) and HCO2H (15 mL) was stirred at room
temperature until a TLC analysis showed that the starting material
was completely consumed (15 min). The resulting mixture was
poured into ice water (50 mL). The water phase was separated and
washed with Et2O (2ꢁ20 mL). Then the combined organic phase
was extracted with water (2ꢁ20 mL). The combined aqueous phase
was mixed with satd NH3 (aq, 25%) until the pH value of the so-
lution was adjusted to be around 8 and then extracted with solution
of CH2Cl2 and MeOH (10/1, 3ꢁ100 mL). The organic phase was
combined, dried over Na2SO4 and concentrated in vacuo to afford
white powder after crystallization in CHCl3 (34.7 g, 85% yield). 1H
b
Determined by HPLC analysis using a chiral column.
was purified by flash chromatography (MeOH/EtOAc¼1/10) to give
a yellowish foam (5.06 g, 95% yield). 1H NMR (400 MHz, CDCl3)
d
8.50 (d, J¼4.5 Hz, 1H), 7.76 (d, J¼9.2 Hz, 1H), 7.51 (d, J¼7.5 Hz, 6H),
7.33e7.11 (m, 12H), 4.90 (d, J¼6.2 Hz, 1H), 3.01e2.79 (m, 3H),
2.47e2.33 (m, 1H), 2.20e2.09 (m, 1H), 1.76e1.62 (m, 1H), 1.54e1.15
(m, 7H), 0.85 (t, J¼7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 154.3,
148.0, 147.5, 144.3, 143.8, 130.6, 128.9, 127.9, 127.4, 126.3, 125.0,
118.7, 111.4, 90.9, 72.0, 59.7, 58.3, 42.8, 37.6, 28.4, 27.7, 25.5, 23.4,
12.2; FT-IR (KBr, cmꢃ1
)
n
2930, 2867, 1617, 1505, 1448, 1234, 1001,
NMR (400 MHz, CD3OD)
d
8.55e8.44 (m, 4H), 8.14 (dd, J¼6.0,

F. Li et al. / Tetrahedron 67 (2011) 10186e10194
10191
O
MeO2C
CO2Me
NO2
MeO2C
NiCl2•6H2O, NaBH4
(a)NaOH(1M), EtOH
NH
MeOH, 0oC
(b)Toluene, Reflux
95% for two steps
93%
Cl
5b
Cl
6
98% yield, 92% e.e.;
87% yield, >99% e.e.
(after single recrystallization)
O
HO2C
NH2•HCl
NH
2D7 =-3.9 (c 0.64, H O).
[
α
]
HCl(6M), Reflux
94%
2
Lit. 2D5 =-3.8 (c 0.65, H O).
[α]
2
Cl
Cl
(R)-(-)-Baclofen hydrochloride(8)
7
Scheme 3. Asymmetric synthesis of (R)-baclofen hydrochloride 8.
3.3 Hz, 2H), 7.93 (d, J¼9.1 Hz, 2H), 7.59e7.48 (m, 4H), 7.38 (dd, J¼9.1,
2.4 Hz, 2H), 7.03 (d, J¼2.9 Hz, 2H), 3.52e3.38 (m, 2H), 3.31e3.16 (m,
2H), 3.05 (dd, J¼13.4,10.1 Hz, 2H), 2.69e2.52 (m, 2H), 2.43e2.31 (m,
2H), 2.10e1.70 (m, 8H),1.61e1.43 (m, 4H),1.42e1.22 (m, 4H), 0.85 (t,
concentrated in vacuo. The residue was purified by flash chroma-
tography (MeOH/CH2Cl2: 1/50 to 1/25 to 1/15) to give a yellowish
foam (5R)-2-((R)-((4-chlorophthalazin-1-yl)oxy)(6-(trityloxy)qui-
nolin-4-yl)methyl)-5-ethylquinuclidine (13.2 g, 96% yield). 1H NMR
J¼7.3 Hz, 6H); 13C NMR (100 MHz, CD3OD)
d
156.5, 145.9, 144.2,
(400 MHz, CDCl3)
d
8.58 (d, J¼4.4 Hz, 1H), 8.33e8.26 (m, 1H),
143.0, 133.1, 130.2, 127.2, 122.7, 122.2, 122.2, 118.3, 104.3, 76.1, 59.2,
8.23e8.09 (m, 1H), 8.02e7.83 (m, 2H), 7.77e7.61 (m, 2H), 7.59e7.44
(m, 6H), 7.36 (d, J¼4.4 Hz, 1H), 7.32e7.15 (m, 9H), 7.10 (dd, J¼9.2,
1.8 Hz, 1H), 6.79 (d, J¼6.5 Hz, 1H), 3.37e3.20 (m, 1H), 3.13e2.85 (m,
2H), 2.60e2.39 (m, 1H), 2.25e2.05 (m, 1H), 1.86e1.20 (m, 8H), 0.88
58.0, 42.6, 37.0, 27.7, 27.1, 25.3, 22.0, 10.9; FT-IR (KBr, cmꢃ1
) n 3072,
2930, 2869, 1620, 1471, 1393, 1092, 851; ½a D29
þ291.7 (c 1.06, EtOH);
ꢂ
ESI-MS (m/z): 751.3 (MþHþ), 457.0 (Mþ2Hþ); HRMS (ESI-MS) for
C46H51N6O4(MþHþ): calcd 751.3976, found 751.3966; Crystallo-
graphic data for Q4 (C48H58N6O6): T¼133 (2) K; Wavelength:
(t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 159.4, 154.9, 150.4,
148.1,145.1,144.2,144.2,133.4,133.2,130.7,129.3,128.1,128.0,127.6,
126.6, 125.8, 125.6, 123.3, 121.8, 119.2, 113.3, 91.6, 78.3, 59.9, 58.7,
ꢀ
0.71073 A; crystal system: tetragonal, space group: P4 (3); unit cell
dimensions: a¼18.8464 (13) A, b¼18.8464 (13) A, c¼24.2401 (16) A,
42.8, 37.7, 29.0, 28.0, 25.8, 24.3,12.4; FT-IR (KBr, cmꢃ1
) n 2925, 2860,
ꢀ
ꢀ
ꢀ
ꢀ
a
¼90ꢀ,
b
¼90ꢀ,
g
¼90ꢀ;
V¼8609.8
(10)
A ;
Z¼8;
1616, 1504, 1394, 1292, 1225, 703; ½a D27
þ124.8 (c 1.06, CHCl3); ESI-
ꢂ
3
rcalcd¼1.257 Mg mꢃ3; F(000)¼3488; final R indices [I>2
s
(I)]:
MS (m/z): 739.2 (MþNaþ), 718.2 (MþHþ); HRMS (ESI) for
R1¼0.0570,
u
R2¼0.1557;
R
indices (all data), R1¼0.0754,
C46H42N4O2Cl (MþHþ): calcd 717.2987, found 717.2991.
u
R2¼0.1717; 48,364 reflections measured, 16,274 were unique
Under N2 atmosphere, to a solution of dried compound dihy-
droquinine (745 mg, 2.3 mmol) in THF (20 mL, freshly distilled in
the presence of Na) was added NaH (183 mg, 60% oil dispersion,
1.2 equiv) in small portions. The resulting mixture was stirred at
room temperature for 2 h. Then the previously obtained in-
termediate (1.80 g, 2.5 mmol) was added in one portion under N2
atmosphere at room temperature. When the reaction was com-
pleted, brine (5 mL) was added to quench. The mixture was added
to water (100 mL) and extracted with EtOAc and washed with water
and brine. The organic phase was dried over Na2SO4 and concen-
trated in vacuo. The residue was purified by flash chromatography
(MeOH/CH2Cl2: 1/15) to afford a yellowish foam (5R)-2-((R)-((4-
chlorophthalazin-1-yl)oxy)(6-(trityloxy)quinolin-4-yl)methyl)-5-
ethylquinuclidine (1.15 g, 50% yield). 1H NMR (400 MHz, CDCl3)
(R(int)¼0.0614). CCDC-826830 (Q4) contains the supplementary
crystallographic data (and details of the data handling and struc-
ture refinement) for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(deMeDHQD)2PHAL QD4 was obtained as a white powder after
crystallization in CHCl3 (82% yield). 1H NMR (400 MHz, CDCl3/
CD3OD)
d
8.51e8.38 (m, 4H), 8.07 (dd, J¼6.0, 3.3 Hz, 2H), 7.93 (d,
J¼9.1 Hz, 2H), 7.46e7.30 (m, 6H), 7.14 (s, 2H), 3.30e3.21 (m, 2H),
2.97e2.78 (m, 6H), 2.77e2.62 (m, 2H), 2.30e2.21 (m, 2H), 1.80 (s,
2H), 1.65e1.31 (m, 12H), 0.86 (t, J¼7.1 Hz, 6H); 13C NMR (100 MHz,
CDCl3/CD3OD)
d 156.3, 156.1, 145.7, 143.8, 142.9, 132.7, 130.4, 126.9,
122.6,122.3,122.3,117.6,104.0, 75.7, 58.7, 50.6, 49.5, 36.8, 26.3, 26.0,
25.0, 21.2, 11.2; FT-IR (KBr, cmꢃ1
)
n
3419, 2931, 2867, 1618, 1516,
d
8.66 (d, J¼4.5 Hz, 1H), 8.57 (d, J¼4.5 Hz, 1H), 8.34 (d, J¼7.8 Hz, 1H),
1387, 1230, 843; ½a D26
ꢂ
ꢃ217.8 (c 0.96, CHCl3/MeOH¼1/1); ESI-MS
8.25 (d, J¼7.9 Hz, 1H), 8.00 (d, J¼9.2 Hz, 1H), 7.94e7.85 (m, 2H), 7.70
(d, J¼9.2 Hz, 1H), 7.61e7.40 (m, 9H), 7.36e7.31 (m, 2H), 7.17e7.04
(m, 11H), 6.49 (d, J¼6.1 Hz, 1H), 3.85 (s, 3H), 3.47 (dd, J¼13.2, 8.1 Hz,
1H), 3.27e2.74 (m, 5H), 2.68e2.29 (m, 4H), 2.07e1.15 (m, 16H),
(m/z): 751.2 (MþHþ), 773.4 (MþNaþ); HRMS (ESI-MS) for
C46H51N6O4(MþHþ): calcd 751.3976, found 751.3966.
4.2.5. [(deMeDHQ)(DHQ)]PHAL Q8. Under N2 atmosphere, to a so-
lution of dried compound Q6 (10.6 g, 18 mmol) in THF (40 mL,
freshly distilled in the presence of Na) was added NaH (866 mg, 60%
oil dispersion, 1.2 equiv) in small portions. The resulting mixture
0.87e0.79 (m, 6H); 13C NMR (100 MHz, CDCl3)
d 158.0, 156.5, 156.3,
154.6,148.1,147.5,145.2,145.1,145.0,144.0,132.4,131.8,130.5,129.2,
128.0, 127.4, 127.3, 126.5, 125.8, 123.1, 122.8, 122.7, 122.6, 122.2,
118.8, 118.4, 113.4, 102.3, 91.5, 76.5, 60.2, 58.7, 55.9, 43.1, 42.8, 37.7,
was stirred at room temperature for
2
h. Then 1,4-
37.6, 28.8, 27.9, 25.7, 25.7, 24.0, 23.1, 12.3, 12.3; ½a D27
þ151.6 (c 1.04,
ꢂ
dichlorophthalazine (3.66 g, 18.4 mmol) was added in one por-
tion under N2 atmosphere at 0 ꢀC. The reaction mixture was then
warmed and kept at room temperature. When the reaction was
completed, brine (5 mL) was added to quench. The mixture was
added to water (100 mL) and extracted with EtOAc and washed
with water and brine. The organic phase was dried over Na2SO4 and
CHCl3); FT-IR (KBr, cmꢃ1
) n 2925, 2862, 1619, 1552, 1353, 1227, 983,
702; ESI-MS (m/z): 1029.5 (MþNaþ), 1007.5 (MþHþ); HRMS (ESI)
for C66H67N6O4(MþHþ): calcd 1007.5218, found 1007.5207.
A mixture of the previously obtained intermediate (1.15 g,
1.14 mmol), Et2O (15 mL) and HCO2H (15 mL) was stirred at room
temperature until a TLC analysis showed that the starting material

10192
F. Li et al. / Tetrahedron 67 (2011) 10186e10194
was completely consumed (15 min). The resulting mixture was
poured into ice water (60 mL). The water phase was separated and
washed with Et2O (3ꢁ30 mL). Then the combined organic phase
was extracted with water (2ꢁ20 mL). The combined aqueous phase
was mixed with satd NH3 (aq, 25%) until the pH value of the so-
lution was adjusted to be around 8 and then extracted with solution
of CH2Cl2 (3ꢁ100 mL). The organic phase was combined, dried over
Na2SO4 and concentrated in vacuo. The residue was purified by
flash chromatography (MeOH/CH2Cl2: 1/15) to afford a yellowish
(MþNaþ); HPLC: Chiralcel OD-H Column (250 mm), detected at
220 nm; hexane/i-propanol¼70/30, flow¼1.0 mL/min, t (major)¼
14.2 min, t (minor)¼18.4 min.
4.3.5. (S)-Dimethyl
2-(1-(2-bromophenyl)-2-nitroethyl)malonate
4e19. White solid: ½a 2D4
ꢂ
þ2.7 (c 1.43, CHCl3, 95% ee); 1H NMR
(400 MHz, CDCl3)
d
7.53 (dd, J¼7.9, 0.8 Hz, 1H), 7.29e7.20 (m, 2H),
7.13e7.02 (m, 1H), 5.05 (dd, J¼13.7, 8.6 Hz, 1H), 4.89 (dd, J¼13.7,
4.5 Hz,1H), 4.70 (td, J¼8.2, 4.5 Hz,1H), 4.04 (d, J¼7.9 Hz,1H), 3.65 (s,
3H), 3.58 (s, 3H); HPLC: Chiralcel OD-H Column (250 mm), detected
at 220 nm, hexane/i-propanol¼70/30, flow¼1.0 mL/min, t (major)¼
9.7 min, t (minor)¼20.6 min.
powder Q8 (785 mg, 90%). 1H NMR (400 MHz, CDCl3)
d 8.61 (d,
J¼4.6 Hz, 1H), 8.55 (d, J¼4.5 Hz, 1H), 8.42e8.35 (m, 1H), 8.30 (d,
J¼7.7 Hz, 1H), 8.00e7.82 (m, 4H), 7.54 (d, J¼2.5 Hz, 1H), 7.51e7.42
(m, 2H), 7.33e7.21 (m, 4H), 7.16 (d, J¼5.0 Hz, 1H), 6.97 (s, 1H), 3.87
(s, 3H), 3.54e3.39 (m, 1H), 3.38e2.99 (m, 3H), 2.89e2.81 (m, 1H),
2.75e2.51 (m, 2H), 2.35 (d, J¼14.4 Hz, 1H), 2.18 (d, J¼12.9 Hz, 1H),
2.01e1.08 (m, 17H), 0.82 (t, J¼7.3 Hz, 3H), 0.75 (t, J¼6.8 Hz, 3H); 13C
4.3.6. (S)-Dimethyl
2-(1-(4-methylphenyl)-2-nitroethyl)malonate
ꢂ
4f5c,17c. White solid: ½a 2D4
þ2.9 (c 1.17, CHCl3, 93% ee); 1H NMR
(400 MHz, CDCl3)
d 7.14e7.09 (m, 4H), 4.93e4.82 (m, 2H), 4.20 (td,
NMR (100 MHz, CDCl3)
d
158.0, 156.5, 156.2, 156.1, 146.8, 146.2,
J¼8.9, 5.3 Hz, 1H), 3.84 (d, J¼9.0 Hz, 1H), 3.76 (s, 3H), 3.58 (s, 3H),
2.30 (s, 3H); HPLC: Chiralcel OD-H Column (250 mm), detected at
220 nm, hexane/i-propanol¼70/30, flow¼1.0 mL/min, t (minor)¼
10.0 min, t (major)¼14.7 min.
145.1,144.1,143.7,143.6,132.5,132.4,131.3,130.8,127.2,122.8,122.6,
122.5, 122.4, 122.3, 119.6, 118.1, 118.1, 118.0, 104.9, 101.9, 75.7, 60.1,
59.1, 58.3, 58.2, 55.7, 42.8, 42.7, 42.6, 37.3, 37.1, 28.4, 28.3, 27.6, 27.3,
25.4, 25.4, 23.0, 21.9, 12.0, 12.0; FT-IR (KBr, cmꢃ1
) n 3583, 3015,
a 27
2350, 1620, 1351, 1229, 930, 776; ½ ꢂD þ306.2 (c 0.86, CHCl3); ESI-
MS (m/z): 765.4 (MþHþ); HRMS (ESI) for C47H53N6O4(MþHþ):
calcd 765.4132, found 765.4123.
4.3.7. (S)-Dimethyl 2-(1-(4-methoxylphenyl)-2-nitroethyl)-malonate
4g5c. White solid: ½a 2D4
ꢂ
þ4.82 (c 1.42, CHCl3, 94% ee); 1H NMR
(400 MHz, CDCl3)
d
7.14 (d, J¼8.7 Hz, 2H), 6.84 (d, J¼8.7 Hz, 2H),
4.94e4.76 (m, 2H), 4.19 (td, J¼9.0, 5.1 Hz, 1H), 3.83 (d, J¼9.1 Hz, 1H),
3.78 (s, 3H), 3.76 (s, 3H), 3.57 (s, 3H); HPLC: Chiralcel OD-H Column
(250 mm), detected at 220 nm; hexane/i-propanol¼70/30,
flow¼1.0 mL/min, t (major)¼13.6 min, t (minor)¼15.6 min.
4.3. General procedure for enantioselective 1,4-addition of
Dimethyl malonate to nitroalkenes
At room temperature, to a solution of nitroalkenes 2 (0.2 mmol)
and chiral catalyst Q4 or QD4 in THF was added dimethyl malonate
4.3.8. (S)-Dimethyl
2-(1-(4-flurophenyl)-2-nitroethyl)malonate
ꢂ
þ5.82 (c 1.18, CHCl3, 90% ee); 1H NMR
3 (68
m
L, 0.3 mmol). The resulting mixture was purified by flash
4h5c. Colorless oil: ½a 2D4
chromatography when 2 was consumed through a TLC analysis to
afford the product 4 or 5.
(400 MHz, CDCl3)
d
7.22 (dd, J¼8.7, 5.2 Hz, 2H), 7.02 (t, J¼8.6 Hz,
2H), 4.97e4.76 (m, 2H), 4.24 (td, J¼9.2, 5.0 Hz,1H), 3.83 (d, J¼9.1 Hz,
1H), 3.76 (s, 3H), 3.57 (s, 3H); HPLC: Chiralcel AD-H Column
(250 mm), detected at 220 nm, hexane/i-propanol¼70/30,
flow¼1.0 mL/min, t (major)¼8.6 min, t (minor)¼17.1 min.
4.3.1. (S)-Dimethyl 2-(2-nitro-1-phenylethyl)malonate 4a5c,17d,e
.
White solid: ½a 2D5
ꢂ
þ6.1 (c 1.1, CHCl3, 94% ee); 1H NMR (400 MHz,
CDCl3)
d
7.41e7.13 (m, 5H), 4.97e4.82 (m, 2H), 4.24 (td, J¼8.9,
5.3 Hz, 1H), 3.87 (d, J¼9.1 Hz, 1H), 3.76 (s, 3H), 3.56 (s, 3H); ESI-MS
(m/z): 281.9 (MþHþ), 304.0 (MþNaþ); HPLC: Chiralcel OD-H Col-
umn (250 mm); detected at 220 nm, hexane/i-propanol¼70/30,
flow¼0.7 mL/min, t (major)¼18.1min, t (minor)¼20.7 min. The
absolute configuration of (þ)-4a was determined as S by compari-
son of the specific rotation of the corresponding literature.17a
4.3.9. (S)-Dimethyl
2-(1-(1-naphthyl)-2-nitroethyl)malonate
4i5c. Colorless oil: ½a 2D4
ꢂ
ꢃ3.74 (c 0.88, CHCl3, 96% ee); 1H NMR
(400 MHz, CDCl3)
d
8.17 (d, J¼8.4 Hz, 1H), 7.88 (d, J¼8.1 Hz, 1H), 7.80
(d, J¼7.9 Hz, 1H), 7.66e7.58 (m, 1H), 7.53 (t, J¼7.1 Hz, 1H), 7.40 (dt,
J¼7.2, 6.7 Hz, 2H), 5.28e5.01 (m, 3H), 4.11 (d, J¼7.5 Hz, 1H), 3.72 (s,
3H), 3.54 (s, 3H); HPLC: Chiralcel OD-H Column (250 mm), detected
at 220 nm; hexane/i-propanol¼70/30, flow¼1.0 mL/min, t (major)¼
17.8 min, t (minor)¼27.7 min.
4.3.2. (S)-Dimethyl
2-(1-(4-chlorophenyl)-2-nitroethyl)malonate
4b5c,17c. White solid: ½a 2D5
ꢂ
þ7.6 (c 1.42, CHCl3, 95% ee); 1H NMR
(400 MHz, CDCl3)
d
7.30 (d, J¼8.5 Hz, 2H), 7.18 (d, J¼8.5 Hz, 2H),
4.3.10. (S)-Dimethyl
2-(1-(2-furyl)-2-nitroethyl)malonate
4j19
.
4.94e4.81 (m, 2H), 4.23 (td, J¼9.1, 5.0 Hz,1H), 3.83 (d, J¼9.0 Hz,1H),
3.76 (s, 3H), 3.59 (s, 3H); HPLC: Chiralcel OD-H Column (250 mm);
detected at 220 nm, hexane/i-propanol¼70/30, flow¼0.7 mL/min, t
(major)¼11.9 min, t (minor)¼16.4 min.
Yellowish oil: ½a D25
ꢂ
ꢃ4.59 (c 0.86, CHCl3, 97% ee); 1H NMR (400 MHz,
CDCl3)
d
7.35 (d, J¼0.6 Hz, 1H), 6.29 (s, 1H), 6.22 (d, J¼3.2 Hz, 1H),
4.98e4.82 (m, 2H), 4.39 (dt, J¼13.1, 6.7 Hz,1H), 3.95 (d, J¼7.8 Hz,1H),
3.76 (s, 3H), 3.69 (s, 3H); HPLC: Chiralcel OD-H Column (250 mm),
detected at 220 nm; hexane/i-propanol¼70/30, flow¼1.0 mL/min, t
(major)¼7.7 min, t (minor)¼18.8 min.
4.3.3. (S)-Dimethyl
2-(1-(2-chlorophenyl)-2-nitroethyl)malonate
4c18e. White solid: ½a 2D9
ꢂ
þ3.2 (c 1.0, CHCl3, 96% ee); 1H NMR
(400 MHz, CDCl3)
d
7.47e7.35 (m, 1H), 7.30e7.18 (m, 3H), 5.12 (dd,
4.3.11. (R)-(E)-Dimethyl 2-(1-nitro-4-phenylbut-3-en-2-yl)malonate
J¼13.7, 8.6 Hz, 1H), 4.96 (dd, J¼13.7, 4.5 Hz, 1H), 4.76 (td, J¼8.5,
4.5 Hz, 1H), 4.12 (d, J¼8.4 Hz, 1H), 3.73 (s, 3H), 3.64 (s, 3H); HPLC:
Chiralcel OD-H Column (250 mm), detected at 220 nm, hexane/i-
propanol¼70/30, flow¼0.7 mL/min, t (major)¼9.1 min, t (minor)¼
19.5 min.
4k5d. White solid: ½a 2D4
ꢂ
þ21.8 (c 1.02, CHCl3, 90% ee); 1H NMR
(400 MHz, CDCl3)
d
7.39e7.18 (m, 5H), 6.58 (d, J¼15.8 Hz, 1H),
6.19e6.01 (m, 1H), 4.81e4.62 (m, 2H), 3.84e3.62 (m, 8H); HPLC:
Chiralcel AD-H Column (250 mm), detected at 220 nm; hexane/i-
propanol¼70/30, flow¼1.0 mL/min, t (major)¼8.8 min, t (minor)¼
10.2 min.
4.3.4. (S)-Dimethyl
2-(1-(4-bromophenyl)-2-nitroethyl)malonate
4d5c. White solid: ½a 2D4
ꢂ
þ6.7 (c 1.2, CHCl3, 94% ee); 1H NMR
4.3.12. (R)-Dimethyl 2-(1-cyclohexyl-2-nitroethyl)malonate 4l5c
.
(400 MHz, CDCl3)
d
7.46 (d, J¼8.4 Hz, 2H), 7.12 (d, J¼8.4 Hz, 2H),
Colorless oil: ½a D23
ꢂ
þ17.7 (c 3.53, CHCl3, 89% ee); 1H NMR (400 MHz,
4.99e4.76 (m, 2H), 4.21 (td, J¼9.0, 5.0 Hz,1H), 3.83 (d, J¼9.0 Hz,1H),
CDCl3)
d
4.73 (dd, J¼14.6, 4.3 Hz, 1H), 4.62 (dd, J¼14.6, 6.5 Hz, 1H),
3.76 (s, 3H), 3.59 (s, 3H); ESI-MS (m/z): 360.0 (MþHþ), 382.1
3.79e3.70 (m, 7H), 2.99e2.78 (m, 1H), 1.86e1.61 (m, 5H), 1.54e1.36

F. Li et al. / Tetrahedron 67 (2011) 10186e10194
10193
(m, 1H), 1.30e0.86 (m, 5H); ESI-MS (m/z): 288.1 (MþHþ), 310.0
(MþNaþ), 326.1 (MþKþ); HPLC: Chiralcel OD-H Column (250 mm),
detected at 215 nm; hexane/i-propanol¼90/10, flow¼1.0 mL/min, t
(major)¼6.6 min, t (minor)¼16.7 min.
EI-MS (m/z): 195 (Mþ, 33.82), 138 (100), 140 (30.94), 103 (20.85),
197 (15.07), 77 (11.69), 139 (11.18), 91 (9.09).
4.4.3. (R)-(ꢃ)-Baclofen hydrochloride 824. To
a solution of 7
(100 mg, 0.51 mmol) and 6 N HCl (2.8 mL) was refluxed for 24 h. The
resulting mixture was concentrated in vacuo to afford (R)-
(ꢃ)-Baclofen hydrochloride 8 (120 mg, 94%). 1H NMR (400 MHz,
4.3.13. (R)-Dimethyl
2-(1-iso-butyl-2-nitroethyl)malonate
4m19.
Colorless oil: ½a D23
ꢂ
þ9.4 (c 0.13, CHCl3, 89% ee); 1H NMR (400 MHz,
CDCl3)
d
4.71 (dd, J¼13.4, 5.3 Hz, 1H), 4.52 (dd, J¼13.4, 6.4 Hz, 1H),
DMSO-d6) d 12.24 (br s, 1H), 8.11 (s, 3H), 7.57e7.13 (m, 4H),
3.80e3.73 (m, 6H), 3.66 (d, J¼5.5 Hz, 1H), 3.08e2.86 (m,1H),1.74e1.56
(m, 1H), 1.39e1.23 (m, 2H), 0.99e0.84 (m, 6H); ESI-MS (m/z): 299.1
(MþKþ); HPLC: Chiralcel OD-H Column (250 mm), detected at 215 nm,
hexane/i-propanol¼90/10; flow¼1.0 mL/min, t (major)¼8.8 min, t
(minor)¼20.1 min.
3.15e3.07 (m, 1H), 3.04e2.92 (m, 1H), 2.86 (dd, J¼16.3 Hz, 5.4 Hz,
1H), 2.57 (dd, J¼16.3, 9.4 Hz, 1H); ½a D26
ꢃ3.9 (c 0.64, H2O); ESI-MS
ꢂ
(m/z): 214.1 (MþHþ).
Acknowledgements
4.3.14. (R)-Dimethyl 2-(1-nitro-4-phenylbutan-2-yl)malonate 4n.
Colorless oil: ½a D23
ꢂ
þ3.0 (c 0.58, CHCl3, 86% ee); 1H NMR (400 MHz,
Financial support from the Major State Basic Research De-
velopment Program 2010CB833302, and the Shanghai Municipal
Committee of Science and Technology 09JC1417300 is greatly
acknowledged.
CDCl3)
d
7.33e7.24 (m, 2H), 7.24e7.10 (m, 3H), 4.74 (dd, J¼13.5,
5.2 Hz, 1H), 4.56 (dd, J¼13.5, 6.6 Hz, 1H), 3.75 (s, 6H), 3.71 (d,
J¼5.9 Hz, 1H), 2.94 (dd, J¼12.2, 5.8 Hz, 1H), 2.69 (td, J¼7.1, 1.5 Hz,
2H),1.80 (dd, J¼15.9, 7.0 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 168.2,
140.2, 128.6, 128.2, 126.4, 52.9, 52.8, 52.3, 36.5, 32.9, 31.7; ESI-MS
(m/z): 310.0 (MþHþ), 332.1(MþNaþ); HRMS (ESI) for
C15H19NNaO6 (MþNaþ): calcd 332.1105, found 332.1117. HPLC:
Chiralcel OD-H Column (250 mm), detected at 215 nm, hexane/i-
propanol¼90/10, flow¼1.0 mL/min, t (major)¼15.1 min, t (minor)¼
19.5 min.
References and notes
1. Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691e1693.
2. For the recent reviews see: (a) Marcelli, T.; Hiemstra, H. Synthesis 2010,
1229e1279; (b) Lee, J. W.; Song, C. E. Cinchona Alkaloids in Synthesis and Ca-
talysis; Wiley-VCH: Weinheim, 2009; (c) Marcelli, T.; van Maarseveen, J. H.;
Hiemstra, H. Angew. Chem., Int. Ed. 2006, 45, 7496e7504; (d) Tian, S. K. i; Chen,
Y. G.; Hang, J. F.; Tang, L.; McDaid, P.; Deng, L. Acc. Chem. Res. 2004, 37, 621e631.
3. For asymmetric MoritaeBayliseHillman reaction see: (a) Zhong, F. R.; Chen, G.
Y.; Lu, Y. X. Org. Lett. 2011, 13, 82e85; (b) Guan, X. Y.; Wei, Y.; Shi, M. Chem.dEur.
J. 2010, 16, 13617e13621; (c) Liu, Y. L.; Wang, B. L.; Cao, J. J.; Chen, L.; Zhang, Y.
X.; Wang, C.; Zhou, J. J. Am. Chem. Soc. 2010, 132, 15176e15178; (d) Nakano, A.;
Takahashi, K.; Ishihara, J.; Hatakeyama, S. Org. Lett. 2006, 8, 5357e5360; (e)
Nakano, A.; Kawahara, S.; Akamatsu, S.; Morokuma, K.; Nakatani, M.; Iwabuchi,
Y.; Takahashi, K.; Ishihara, J.; Hatakeyama, S. Tetrahedron 2006, 62, 381e389; (f)
Shi, M.; Jiang, J. K. Tetrahedron: Asymmetry 2002, 13, 1941e1947; (g) Iwabuchi,
Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121,
10219e10220.
4.3.15. (þ)-Dimethyl
2-(2-nitro-1-(4-nitrophenyl)ethyl)malonate
4o5d. White solid: ½a 2D7
ꢂ
þ7.1 (c 0.99, CHCl3); 1H NMR (400 MHz,
CDCl3)
d
8.21 (d, J¼8.7 Hz, 2H), 7.46 (d, J¼8.7 Hz, 2H), 5.02e4.84 (m,
2H), 4.37 (td, J¼8.7, 5.5 Hz, 1H), 3.88 (d, J¼8.8 Hz, 1H), 3.78 (s, 3H),
3.61 (s, 3H); ESI-MS (m/z): 349.1 (MþNaþ); HPLC: Chiralcel OD-H
Column (250 mm), detected at 220 nm, n-hexane/i-propanol¼80/
20, flow¼1.0 mL/min, t (major)¼19.4 min, t (minor)¼30.6 min.
4. For asymmetric Aza-MoritaeBayliseHillman reaction see: (a) Guan, X. Y.; Wei,
Y.; Shi, M. Eur. J. Org. Chem. 2010, 4098e4105; (b) Shi, M.; Qi, M. J.; Liu, X. G.
Chem. Commun. 2008, 6025e6027; (c) Shi, M.; Xu, Y. M.; Shi, Y. L. Chem.dEur. J.
2005, 11, 1794e1802; (d) Kawahara, S.; Nakano, A.; Esumi, T.; Iwabuchi, Y.;
Hatakeyama, S. Org. Lett. 2003, 5, 3103e3105; (e) Shi, M.; Xu, Y. M. Angew.
Chem., Int. Ed. 2002, 41, 4507e4510.
5. For asymmetric conjugate addition to nitroalkenes see: (a) Shi, M.; Lei, Z. Y.;
Zhao, M. X.; Shi, J. W. Tetrahedron Lett. 2007, 48, 5743e5746; (b) Li, H. M.; Wang,
Y.; Tang, L.; Wu, F. H.; Liu, X. F.; Guo, C. Y.; Foxman, B. M.; Deng, L. Angew. Chem.,
Int. Ed. 2005, 44, 105e108; (c) Li, H. M.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem.
Soc. 2004, 126, 9906e9907; (d) Li, X.-J.; Liu, K.; Ma, H.; Nie, J.; Ma, J.-A. Synlett
2008, 3242e3246.
4.4. Preparation of (R)-(L)-baclofen hydrochloride 8
4.4.1. (4R)-Methyl 4-(4-chlorophenyl)-2-oxopyrrolidine-3-
carboxylate 6. Under Ar atmosphere, to a solution of 5b (316 mg,
1 mmol, >99% ee) and NiCl2$6H2O (238 mg, 1 mmol) in methanol
(5 mL) was added NaBH4 (454 mg, 12 mmol) at 0 ꢀC. The resulting
mixture was kept at room temperature until the 5b was consumed.
The reaction was quenched with NH4Cl (aq) and diluted with CHCl3.
The organic phase was separated and extracted with CHCl3. The
combined organic phase dried over Na2SO4 and concentrated in
vacuo. The residue was purified by chromatography on silica gel
(CH2Cl2/MeOH¼15/1) to give product 6 (235 mg, 93%). 1H NMR
6. For asymmetric conjugate addition to a,b-unsaturated aldehydes, ketones, cy-
anides and sulfones see: (a) Wu, F. H.; Hong, R.; Khan, J. H.; Liu, X. F.; Deng, L.
Angew. Chem., Int. Ed. 2006, 45, 4301e4305; (b) Wu, F. H.; Hong, R.; Deng, L.
Angew. Chem., Int. Ed. 2006, 45, 947e950; (c) Wang, Y.; Liu, X. F.; Deng, L. J. Am.
Chem. Soc. 2006, 128, 3928e3930; (d) Li, H. M.; Song, J.; Liu, X. F.; Deng, L. J. Am.
Chem. Soc. 2005, 127, 8948e8949.
7. For asymmetric Henry reaction see: (a) Li, H. M.; Wang, B. M.; Deng, L. J. Am.
Chem. Soc. 2006, 128, 732e733; (b) Bandini, M.; Sinisi, R.; Umani-Ronchi, A.
Chem. Commun. 2008, 4360e4362; (c) Marcelli, T.; van der Haas, R. N. S.; van
Maarseveen, J. H.; Hiemstra, H. Synlett 2005, 2817e2819.
(400 MHz, CDCl3)
d
7.32 (d, J¼8.5 Hz, 2H), 7.20 (d, J¼8.4 Hz, 2H),
4.09 (dd, J¼17.8, 8.6 Hz, 1H), 3.85e3.74 (m, 4H), 3.54 (d, J¼9.7 Hz,
1H), 3.40 (t, J¼8 Hz, 1H); ½a D29
ꢃ126.8 (c 1.15, CHCl3); ESI-MS (m/z):
ꢂ
276.0 (MþNaþ).
8. For asymmetric Mannich reaction see: (a) Cheng, L.; Kiu, L.; Jia, H.; Wang, D.;
Chen, Y. J. J. Org. Chem. 2009, 74, 4650e4653; (b) Ricci, A.; Pettersen, D.; Ber-
nardi, L.; Fini, F.; Fochi, M.; Herrera, R. P.; Sgarzani, V. Adv. Synth. Catal. 2007,
349, 1037e1040.
9. For asymmetric allylic nucleophilic substitution see: (a) Peng, J.; Huang, X.; Cui,
H. L.; Chen, Y. C. Org. Lett. 2010, 12, 4260e4263; (b) van Steenis, D. J. V. C.;
Marcelli, T.; Lutz, M.; Spek, A. L.; van Maarseveen, J. H.; Hiemstra, H. Adv. Synth.
Catal. 2007, 349, 281e286; (c) Du, Y. S.; Han, X. L.; Lu, X. Y. Tetrahedron Lett.
2004, 45, 4967e4971.
10. For asymmetric DielseAlder reaction see: Wang, Y.; Li, H. M.; Wang, Y. Q.; Liu,
Y.; Foxman, B. M.; Deng, L. J. Am. Chem. Soc. 2007, 129, 6364e6365.
11. For asymmetric formal [3þ2] cycloaddition reaction see: Guo, C.; Xue, M. X.;
Zhu, M. K.; Gong, L. Z. Angew. Chem., Int. Ed. 2008, 47, 3414e3417.
12. For asymmetric Kornblum DeLaMare rearrangement reaction see: Staben, S. T.;
Xin, L. H.; Toste, F. D. J. Am. Chem. Soc. 2006, 128, 12658e12659.
4.4.2. (R)-4-(4-Chlorophenyl)pyrrolidin-2-one 718b. To a solution of
6 (200 mg, 0.78 mmol) and EtOH (2.8 mL) was added 1 N NaOH
(0.9 mL) at room temperature. The resulting mixture was concen-
trated in vacuo when 6 was consumed. To the residue was added
water (5 mL) and 5 N HCl. The pH value of the solution was de-
termined to be around 3. The aqueous phase was extracted with
CHCl3 and dried over Na2SO4 and concentrated in vacuo. To the
solution of resultant in toluene (10 mL) was refluxed. After 8 h, the
mixture was concentrated in vacuo and the residue was purified by
chromatography on silica gel (CHCl3/MeOH¼7/1) to give the white
solid 7 (147 mg, 95%). 1H NMR (400 MHz, CDCl3)
d
7.32 (d, J¼8.4 Hz,
13. For asymmetric a-amination reaction see: Saaby, S.; Bella, M.; Jérgensen, K. A. J.
2H), 7.19 (d, J¼8.4 Hz, 2H), 6.44 (br s, 1H), 3.79 (t, J¼8.8 Hz, 1H),
Am. Chem. Soc. 2004, 126, 8120e8121.
14. Kolb, H. C.; Andersson, P. G.; Sharpless, K. B. J. Am. Chem. Soc. 1994, 116,
1278e1291.
3.73e3.62 (m, 1H), 3.38 (dd, J¼9.3, 7.2 Hz, 1H), 2.74 (dd, J¼16.9,
8.9 Hz, 1H), 2.45 (dd, J¼16.9, 8.6 Hz, 1H); ½a D26
ꢃ35.7 (c 0.92, EtOH);
ꢂ

10194
F. Li et al. / Tetrahedron 67 (2011) 10186e10194
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112e124.
16. Lin, G. Q.; Li, F.; Tian, P.; Xu, M. H.; Jia, Z. S. Chinese Patent CN101869846A, Oct.
27, 2010.
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A.; Gomez-Bengoa, E.; Najera, C. J. Org. Chem. 2009, 74, 6163e6168.
21. Q8 was synthesized by separate steps of coupling Q5a and then DHQ with PHAL
and subsequent deprotection of Trt-group of the product.
22. The distances between the two phenolic O atoms in two Q4 molecules are
different, because two conformations exist in the lattice. One Q4 (O5 and O8) is
in the center and the other one (O1 and O4) is at the corner.
23. (a) Olpe, H. R.; Demieville, H.; Baltzer, V.; Bencze, W. L.; Koella, W. P.; Wolf, P.;
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