Enantioselective Michael reaction of nitroalkanes onto nitroalkenes catalyzed by cinchona alkaloid derivatives

Article abstract of DOI:10.1016/j.tetasy.2012.11.008

An effective asymmetric synthesis of optically active 1,3-dinitro compounds via the direct Michael addition of nitroalkanes onto nitroalkenes has been described. In the presence of readily modified cinchona alkaloid derivatives, nitroethane reacted well w

Full text of DOI:10.1016/j.tetasy.2012.11.008

Tetrahedron: Asymmetry 23 (2012) 1647–1652
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Enantioselective Michael reaction of nitroalkanes onto nitroalkenes
catalyzed by cinchona alkaloid derivatives
Yan-Qiu Deng a, Zhen-Wei Zhang a, Ya-Hui Feng a, Albert S. C. Chan a, Gui Lu a,b,
⇑
a Institute of Medicinal Chemistry, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China
b Institute of Human Virology, Sun Yat-sen University, Guangzhou 510080, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 September 2012
Accepted 11 November 2012
An effective asymmetric synthesis of optically active 1,3-dinitro compounds via the direct Michael addi-
tion of nitroalkanes onto nitroalkenes has been described. In the presence of readily modified cinchona
alkaloid derivatives, nitroethane reacted well with a variety of aromatic and heterocyclic aromatic nitro-
alkenes to afford products with good diastereoselectivities (dr up to 72/28) and enantioselectivities (ee
up to 94%). The catalyst loading can be decreased to 2 mol % without compromising the asymmetric
induction or the reaction rate.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
Du et al. reported a chiral squaramide-catalyzed enantioselective
Michael reaction of nitroalkanes to nitroalkenes.16 Toy et al. used
The Michael reaction of stabilized carbanions to
a
,b-unsatu-
amine-thiourea bifunctional polymeric organocatalysts for this
reaction.17 Additionally, Maruoka et al. achieved an efficient conju-
gate addition of silyl nitronates onto nitroalkenes using a phase-
transfer catalyst.18 Despite these successes, the development of effi-
cient catalytic systems with readily prepared catalysts, low catalyst
loading, and mild reaction conditions remains a challenge.
On the other hand, cinchona derivatives have already been used
to catalyze a wide range of chemical reactions, often with remark-
able stereoselectivity.19 Although Wang et al. have proved that the
presence of two –OH groups (60-OH, 9-OH) in the cinchona alkaloid
Q-1 is necessary for achieving high enantioselectivity for the con-
jugate addition reaction of nitroalkanes with nitroolefins,13 we also
noticed that some cinchona derivatives that lacked either a 9-OH
or a 60-OH served as effective catalysts for some structurally re-
lated Michael reactions, such as 1,3-dicarbonyl compounds to
nitroalkenes.20–23
rated systems is one of the most valuable reactions in organic syn-
thesis, which allows the efficient construction of new carbon–
carbon bonds. In recent years, catalytic enantioselective Michael
reactions have been widely investigated, a,b-unsaturated carbonyl
compounds, nitroalkenes, and some activated olefins are usually
chosen as Michael acceptors, while nitroalkanes and activated
methylene compounds are used as Michael donors.1–6 However,
the direct Michael addition of nitroalkanes onto nitroalkenes is
rather rare despite the fact that the 1,3-dinitro compounds are use-
ful synthetic intermediates, which can be readily transformed into
a variety of functionalities.7–10
In 2006, Du et al. reported the first catalytic enantioselective con-
jugate addition of nitroalkanes onto nitroolefins using Et2Zn/
Ti(OiPr)4/bis(oxazoline) or bis(thiozoline) as the chiral catalyst.11
However, this system is not suitable for highly sterically hindered
nitroalkanes because of their decreased nucleophilic activities. Feng
et al. developed another efficient metal-catalyzed system for this
Michael reaction by using a chiral La(OTf)3/N,N0-dioxide complex.12
Some groups have focused on this asymmetric reaction and devel-
oped a number of efficient organocatalytic systems. Wang et al. were
the first to propose an organocatalytic enantioselective Michael
reaction using cinchona alkaloid-derived catalyst Q-1,13 albeit
10 mol % catalyst loading and a long reaction time (6 days) were
needed to ensure good stereoselectivities. Wulff14 and Wang15 have
independently developed organocatalytic processes with excellent
asymmetric inductions utilizing bifunctional thiourea catalysts.
In our previous work, we have already synthesized a series of
cinchona alkaloid derived catalysts, and found that QD-2 without
a 9-OH group exhibited good catalytic activity in the asymmetric
Mannich-type reactions of isocyanoacetates to imines.24 Cinchona
alkaloids can activate electrophiles in several ways via both cova-
lent and nonvalent interactions. Small modifications on the cin-
chona scaffold can have
a dramatic impact on both the
diastereoselectivity and the enantioselectivity. Herein we want to
further explore the performance of 9-substituted cinchona alkaloid
on the direct Michael reaction of nitroalkanes onto nitroolefins. Se-
lected organocatalysts include those with different sterically hin-
dered protecting groups at the 9-position of the cinchona
alkaloids while bearing a hydroxyl group or another hydrogen-
bonding donor at the 60-position (Fig. 1).
⇑
Corresponding author. Tel./fax: +86 20 39943048.
E-mail address: lugui@mail.sysu.edu.cn (G. Lu).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.11.008

1648
Y.-Q. Deng et al. / Tetrahedron: Asymmetry 23 (2012) 1647–1652
O
O
BnO
N
R
O
N
HO
N
R
O
N
H
N
H
N
9
6'
HO
HO
HO
S
N
N
N
N
Q-1
QD-7
QD-2: R = Me
QD-3: R = Et
QD-4: R = iPr
Q-5: R = Me
Q-6: R = Ph
Figure 1. Cinchona alkaloid catalysts used herein.
protecting group at the 9-position and the hydrogen-bonding do-
nor at the 60-position play important roles in achieving high
enantioselectivity.
2. Results and discussion
2.1. Optimization of the reaction conditions
Further screening of the reaction conditions showed that the
solvent significantly affected the enantioselectivity. Toluene ap-
peared to be the optimal solvent in terms of the reaction time,
yield, enantioselectivity and diastereoselectivity (entries 7–15).
On the other hand, both the enantioselectivity and diastereoselec-
tivity decreased in the absence of any organic solvent (entry 7). A
decrease in temperature to 0 °C had no significant effect on the
ee or dr values but decreased the activity (entry 16). At 2 mol %
or even 0.5 mol % catalyst loading, the ee and dr values were com-
parable with those of 5 mol % loading, whereas a catalyst loading of
10 or 20 mol % reduced the diastereoselectivity (entries 17–21).
Moreover, no oligomerization was observed in this study.14
The process of the QD-2 catalyzed asymmetric Michael addition
of nitroalkanes to nitroalkenes was also monitored (Table 2). The
Initially, all of the catalysts tested catalyzed the reactions in
moderate to high ee values (50–81%) and satisfactory yields (76–
96%) at 5 mol % catalyst loading in toluene (Table 1, entries 1–6).
Catalysts QD-2 and Q-5 showed the highest catalytic activities,
yielding the major syn-products with opposite absolute configura-
tions,11–13,15 that is, (2R,3R) for QD-2 and (2S,3S) for Q-5 (entries 1
and 4). For QD-3 and QD-4, which have more hindered protecting
groups at the 9-position, the dr and ee values decreased slightly
(entries 2 and 3). Meanwhile, a longer reaction time was needed
for Q-6, which has a benzoyl group at the 9-position (entry 5).
For QD-7, the reaction resulted in a high yield but a lower ee value
when thiourea was used as the hydrogen-bonding donor at the 60-
position (entry 6). These results suggest that the structures of the
Table 1
Optimization of the reaction conditionsa
Me
NO2
*
*
NO2
NO2
catalyst (x mol %)
solvent, 30°C
Me
NO2
9a
Solvent
8a
10aa
Entry
Catalyst
Catalyst loading (mol %)
Time (h)
Yieldb (%)
drc (syn/anti)
ee of synd (%)
1
2
3
4
5
6
7
8
QD-2
QD-3
QD-4
Q-5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
2
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
—
DCE
CHCl3
DCM
THF
48
48
48
48
72
24
24
24
24
24
120
96
120
48
48
72
48
48
120
30
82
85
78
80
76
96
95
78
76
80
65
61
70
72
60
80
85
75
58
94
96
66/34
69/31
72/28
66/34
60/40
66/34
54/46
59/41
58/42
59/41
62/38
56/44
57/43
56/44
58/42
62/38
67/33
58/42
66/34
50/50
51/49
81 (2R,3R)
78 (2R,3R)
77 (2R,3R)
81 (2S,3S)
80 (2S,3S)
50 (2R,3R)
74 (2R,3R)
78 (2R,3R)
76 (2R,3R)
76 (2R,3R)
80 (2R,3R)
70 (2R,3R)
74 (2R,3R)
24 (2R,3R)
5 (2R,3R)
Q-6
QD-7
QD-2
QD-2
QD-2
QD-2
QD-2
QD-2
QD-2
QD-2
QD-2
QD-2
QD-2
QD-2
QD-2
QD-2
QD-2
9
10
11
12
13
14
15
16e
17
18
19
20
21
MTBE
Acetone
iPrOH
DMF
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
83 (2R,3R)
81 (2R,3R)
83 (2R,3R)
83 (2R,3R)
81 (2R,3R)
82 (2R,3R)
1
0.5
10
20
18
a
Unless otherwise indicated, the reactions were performed with nitroethane (30 mmol, 30 equiv), trans-b-nitrostyrene (149 mg, 1 mmol), and the catalyst (5 mol %) in the
solvent (2.5 mL).
b
Isolated yields.
c
Determined by 1H NMR.
d
Determined by HPLC.
Reaction at 0 °C.
e

Y.-Q. Deng et al. / Tetrahedron: Asymmetry 23 (2012) 1647–1652
1649
Table 2
2 h; however, 15% and 21% of the anti-product formed after 48
and 72 h, respectively. These results showed that both the inherent
difficulty of controlling the diastereoselectivity and the epimeriza-
tion of the syn-product caused the moderate dr value in the asym-
metric Michael reaction.
Michael addition of nitroethane to b-nitrostyrene in the presence of catalyst QD-2a
Me
NO2
NO2
*
*
QD-2 (2 mol%)
NO2
Me
NO2
PhMe, 30 o
C
8a
9a
2.2. Substrate scope and limitation
10aa
The scope of the asymmetric Michael reaction of nitroalkanes to
nitroalkenes was then investigated. As shown in Table 3, a wide ar-
ray of aromatic nitroalkenes reacted smoothly with nitromethane
to afford the corresponding 1,3-dinitro compounds with high
enantioselectivities (up to 94% ee). The electronic character of
the substituent group on the phenyl had a marginal effect on the
dr and ee values, but exhibited a significant effect on the reaction
rate. Substrates with electron-withdrawing groups reacted faster
than those with electron-donating groups (entries 2–10). Heteroar-
omatic nitroalkenes were also able to participate in the reaction:
furanyl and thienyl nitroalkenes gave 80% and 94% ee, respectively
Entry
Time (h)
Yield (%)
dr (syn/anti)
1
2
3
4
5
2
6
12
24
48
15
38
60
80
85
77/23
75/25
72/28
69/31
67/33
a
The reaction was performed using nitroethane (30 mmol, 30 equiv), trans-b-
nitrostyrene (149 mg, 1 mmol), and QD-2 (2 mol %) in toluene (2.5 mL).
dr value was 77/23 during the first 2 h and was then significantly
reduced to 67/33 after 48 h.
In addition, epimerization of syn-10aa was also investigated
(Scheme 1). Almost no epimerization was observed in the first
(entries 11 and 12). a,b-Unsaturated nitroolefin 9n was also a via-
ble substrate (entry 14). Aliphatic nitroolefin 9m proved to be
quite inert in this catalytic system, affording low yield (20% even
after 5 days) and moderate enantioselectivity (entry 13). The
Me
NO2
NO2
Me
NO2
NO2
Me
NO2
NO2
QD-2
(2 mol %)
PhMe, 30 °C
10aa
syn-
10aa
syn-
10aa
anti-
time
syn/anti
2 h
97/3
24 h
48 h
72 h
89/11
85/15
79/21
Scheme 1. Epimerization of the syn-10aa.
Table 3
Michael addition of nitroalkanes to nitroalkenes in the presence of catalyst QD-2a
Me
R1
R2
NO2
NO2
Me
QD-2 (2 mol%)
PhMe, 30 o
NO2
R2
R1
NO2
C
8
10
9
Entry
R1
R2
Phenyl 9a
Time (days)
Yieldb (%)
drc (syn/anti)
ee of synd (%)
1
2
3
4
5
6
7
8
H 8a
H 8a
H 8a
H 8a
H 8a
H 8a
H 8a
H 8a
H 8a
H 8a
H 8a
H 8a
H 8a
H 8a
Me 8b
2
2
2
2
2
2
2
2
5
5
3
3
5
2
4
85
87
83
87
82
85
80
84
76
73
80
82
20
80
60
67/33
60/40
55/45
62/38
60/40
72/28
57/43
60/40
54/46
58/42
60/40
60/40
52/48
60/40
—
81
81
80
77
82
74
83
80
82
84
80
94
79
65
83
4-Bromophenyl 9b
2-Chlorophenyl 9c
3-Chlorophenyl 9d
4-Chlorophenyl 9e
2-Fluorophenyl 9f
3-Fluorophenyl 9g
4-Fluorophenyl 9h
4-Methylphenyl 9i
4-Methoxyphenyl 9j
2-Furyl 9k
9
10
11
12
13
14
15e
2-Thienyl 9l
i-Pr 9m
Cinnamyl 9n
Phenyl 9a
a
b
c
Unless otherwise indicated, the reactions were performed using nitroalkane (30 mmol, 30 equiv), nitroalkene (1 mmol), and QD-2 (2 mol %) in PhMe (2.5 mL).
Isolated yield.
Determined by 1H NMR.
Determined by HPLC.
With 20 mol % catalyst.
d
e

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Y.-Q. Deng et al. / Tetrahedron: Asymmetry 23 (2012) 1647–1652
Me
R1
R2
NO2
NO2
tetramethylsilane (TMS, d = 0.00 ppm) as the internal standard.
Chemical shifts are reported as parts per million (ppm) in the
d scale downfield from TMS. 13C NMR spectra were recorded
on a Bruker spectrometer with complete proton decoupling,
and chemical shifts are reported in ppm from TMS with the sol-
vent as the internal reference (CDCl3, d = 77.0 ppm). HPLC analy-
ses were conducted on a Shimadzu 10A instrument using Daicel
Chiralcel OD-H, Chiralpak AD-H or AS-H column (0.46 cm diam-
eter ꢀ 25 cm length). Optical rotations were recorded on a Per-
kin–Elmer polarimeter (Model 341). Analytical TLC was
performed using EM separations percolated silica gel 0.2 mm
layer UV 254 fluorescent sheets.
Me
catalyst
NO2
R2
R1
NO2
9
10
8
QD-2
QD-2
protonation
N
O
N
RO
N
RO
N
H
H
H
H
H
nucleophilic
addition
H
4.2. Procedures for the preparation of the catalysts
O
O
H
H
O
N
N
4.2.1. (S)-(6-Hydroxyquinolin-4-yl)((2S,4S,5R)-5-vinylquinu-
clidin-2-yl)methyl acetate QD-226
O
O
H
O
N
H
R1
O
O
N
R2
Under nitrogen, O-acetylquinidine27 (1.06 g, 2.9 mmol) was dis-
solved in CH2Cl2 (20 mL) at ꢁ78 °C. Next, BBr3 (1.6 mL, 12 mmol) in
CH2Cl2 (15 mL) was added dropwise to the reaction flask and stir-
red for 1 h, then gradually warmed to room temperature and stir-
red overnight. Ammonia water (25%, 10 mL) was added dropwise
into the mixture at 0 °C, and stirred for 15 min before adding water
(10 mL), the water layer was separated and washed with CH2Cl2
(3 ꢀ 10 mL), the organic layer was combined and washed with sat-
urated brine and dried over anhydrous Na2SO4. The solvent was re-
moved under reduced pressure, purified by column
chromatography (ethyl acetate/ammonia water 80:1, V/V) to give
R1
O
Me
R2
Me
II
I
Figure 2. Possible mechanism for the asymmetric Michael reaction.
addition of sterically hindered 2-nitropropane to trans-b-nitrosty-
rene in the presence of 20 mol % QD-2 gave 83% ee; however, the
reaction was slow (entry 15).
QD-2 as a white solid (705 mg, 70% yield). ½a D20
¼ þ110:1 (c 0.4,
ꢂ
CH2Cl2). 1H NMR (400 MHz, CDCl3): d 8.67 (d, J = 4.5 Hz, 1H), 7.96
(d, J = 9.1 Hz, 1H), 7.56 (d, J = 2.4 Hz, 2H, OH), 7.32–7.23 (m, 2H),
6.53 (d, J = 5.8 Hz, 1H), 6.03–5.94 (m, 1H), 5.10–5.06 (m, 2H),
3.30–3.24 (m, 1H), 3.00–2.93 (m, 2H), 2.81–2.71 (m, 2H), 2.31–
2.27 (m, 1H), 2.10 (s, 3H), 1.97–1.86 (m, 1H), 1.80 (s, 1H), 1.54–
1.47 (m, 2H), 1.42–1.34 (m, 1H). 13C NMR (100 MHz, CDCl3): d
169.7, 156.3, 146.2, 143.5, 143.3, 139.9, 131.2, 127.2, 122.6,
118.5, 115.1, 105.6, 73.8, 58.5, 49.7, 49.0, 39.5, 27.8, 26.0, 22.7,
21.1.
2.3. Possible mechanism for the asymmetric Michael reaction
The possible mechanism for the cinchona alkaloid-catalyzed
Michael reactions is proposed in Figure 2.20,25 The chiral base first
captures the a-proton of the nitroalkane to form an activated carb-
anion. Meanwhile, organocatalyst QD-2 adopts a conformation
which simultaneously activates and orientates the Michael donor
and the acceptor by means of double hydrogen bond interactions
(transition state I). After nucleophilic attack of the carbanion to
the nitroalkene, transition state II forms and finally releases the
chiral base to afford 1,3-dinitro compounds.
4.2.2. (S)-(6-Hydroxyquinolin-4-yl)((2S,4S,5R)-5-vinylquinu-
26
clidin-2-yl)methyl propionate QD-3
QD-3 was prepared from O-propionylquinidine28according to
the literature procedure and similar to QD-2, white solid, 50% yield
3. Conclusions
for two steps. ½a D20
ꢂ
¼ þ99:0 (c 0.4, CH2Cl2). 1H NMR (400 MHz,
In conclusion, we have developed an effective asymmetric syn-
thesis of optically active 1,3-dinitro compounds via the Michael
addition of nitroalkanes to nitroalkenes, to afford the correspond-
ing adducts with 72/28 dr and up to 94% ee. The catalytic system
performs well with a broad variety of substrates, and the catalyst
loading can be decreased to 2 mol % without compromising the
asymmetric induction or the reaction rate. Further investigation
on defining the scope and expanding the synthetic utility of this
reaction system is currently in progress.
CDCl3): d 8.67 (d, J = 4.5 Hz, 1H), 7.97 (d, J = 9.1 Hz, 1H), 7.55 (d,
J = 2.5 Hz, 1H), 7.33–7.25 (m, 2H), 6.58 (d, J = 5.3 Hz, 1H), 6.07–
5.92 (m, 2H), 5.14–5.05 (m, 2H), 3.32–3.22 (m, 1H), 3.00 (d,
J = 9.7 Hz, 2H), 2.89–2.68 (m, 2H), 2.42 (q, J = 7.5 Hz, 2H), 2.29
(dd, J = 8.1, 16.2 Hz, 1H), 1.99–1.88 (m, 1H), 1.81 (s, 1H), 1.59–
1.44 (m, 2H), 1.42–1.31 (m, 1H), 1.15 (t, J = 7.6 Hz, 3H). 13C NMR
(100 MHz, CDCl3): d 173.0, 156.4, 146.3, 143.6, 143.0, 139.7,
131.4, 126.9, 122.6, 117.8, 115.2, 104.8, 73.5, 58.3, 49.7, 49.0,
39.3, 27.8, 27.8, 25.8, 21.9, 9.0.
4. Experimental
4.1. General
4.2.3. (S)-(6-Hydroxyquinolin-4-yl)((2S,4S,5R)-5-vinylquinu-
clidin-2-yl)methyl isobutyrate QD-426
QD-4 was prepared from O-isobutyrylquinidine according to
the literature procedure and similar to QD-2, white solid, 60%
yield. ½a 2D0
ꢂ
¼ þ89:5 (c 0.4, CH2Cl2). 1H NMR (400 MHz, CDCl3):
Unless otherwise stated, commercial reagents purchased from
Alfa Aesar, Acros, Aldrich or Shanghai Aladdin chemical compa-
nies were used without further purification. Purification of the
reaction products was carried out by flash chromatography using
Qing Dao Sea Chemical Reagent silica gel (200–300 mesh). 1H
NMR spectra were recorded on a Bruker Avance III spectrometer
(400 MHz) and the spectra were referenced internally to the
residual proton resonance in CDCl3 (d = 7.26 ppm), or with
d
8.67 (d, J = 4.5 Hz, 1H), 7.94 (d, J = 9.1 Hz, 1H), 7.54 (d,
J = 2.5 Hz, 1H), 7.29 (d, J = 4.6 Hz, 1H), 7.22 (dd, J = 2.4, 9.1 Hz,
1H), 6.51 (d, J = 5.7 Hz, 1H), 6.00 (m, 2H), 5.15–5.01 (m, 2H),
3.25 (dd, J = 9.0, 14.9 Hz, 1H), 3.04–2.93 (m, 2H), 2.86–2.56 (m,
3H), 2.28 (q, J = 8.5 Hz, 1H), 1.95–1.86 (m, 1H), 1.81 (s, 1H),
1.50–1.33 (m, 3H), 1.18 (dd, J = 3.8, 7.0 Hz, 6H). 13C NMR
(100 MHz, CDCl3): d 175.7, 156.1, 146.3, 143.6, 143.6, 139.8,

Y.-Q. Deng et al. / Tetrahedron: Asymmetry 23 (2012) 1647–1652
1651
131.3, 127.2, 122.5, 118.3, 115.1, 105.5, 73.6, 58.6, 49.6, 49.1,
39.5, 34.2, 27.7, 26.0, 22.8, 18.9, 18.8.
5:95, flow rate 1.0 mL/min, UV detection at 208 nm, tmajor
(2R,3R) = 32.5 min, tminor (2S,3S) = 35.4 min.
4.2.4. (R)-(6-Hydroxyquinolin-4-yl)((2S,4S,5R)-5-vinylquinu-
clidin-2-yl)methyl acetate Q-526
4.3.2. (2R,3R)-1,3-Dinitro-2-(4-bromophenyl)butane 10ab12
½
a 2D0
ꢂ
¼ þ8:5 (c 1.13, CH2Cl2). 1H NMR (400 MHz, CDCl3): d 7.50
Q-5 was prepared from O-acetylquinine27 according to the liter-
(d, J = 8.4 Hz, 2H), 7.04 (d, J = 8.4 Hz, 2H), 4.98–4.86 (m, 2H), 4.79
(dd, J = 8.4, 13.6 Hz, 1H), 3.99 (dd, J = 6.3, 14.5 Hz, 1H), 1.59 (d,
J = 6.7 Hz, 3H). 13C NMR (100 MHz, CDCl3): d 132.5, 129.6, 123.3,
83.9, 76.0, 46.9, 16.8. HPLC conditions: Daicel Chiralcel OD-H, i-
PrOH/hexane 30:70, flow rate 0.8 mL/min, UV detection at
208 nm, tmajor (2R,3R) = 16.8 min, tminor (2S,3S) = 36.9 min.
ature procedure and similar to QD-2, white solid, 58% yield. 1H
NMR (400 MHz, CDCl3):
d 8.67 (d, J = 4.5 Hz, 1H), 7.97 (d,
J = 9.2 Hz, 1H), 7.55 (d, J = 2.6 Hz, 1H), 7.34–7.25 (m, 2H), 6.57 (d,
J = 5.7 Hz, 1H), 6.05–5.96 (m, 2H), 5.13–5.08 (m, 2H), 3.34–3.26
(m, 1H), 3.05–2.91 (m, 2H), 2.83–2.69 (m, 2H), 2.32–2.26 (m,
1H), 2.12 (s, 3H), 1.98–1.85 (m, 1H), 1.82 (s, 1H), 1.57–1.45 (m,
2H), 1.40–1.32 (m, 1H).
4.3.3. (2R,3R)-1,3-Dinitro-2-(2-chlorophenyl)butane 10ac12
½
a 2D0
ꢂ
¼ þ12:0 (c 1.12, CH2Cl2). 1H NMR (400 MHz, CDCl3): d
4.2.5. (R)-(6-Hydroxyquinolin-4-yl)((2S,4S,5R)-5-vinylquinu-
clidin-2-yl)methyl benzoate Q-626,29
7.46–7.40 (m, 1H), 7.26–7.13 (m, 3H), 5.18–5.06 (m, 1H), 4.89
(dd, J = 1.2, 6.8 Hz, 2H), 4.75–4.67 (m, 1H), 1.59 (d, J = 6.8 Hz, 3H).
13C NMR (100 MHz, CDCl3): d 134.5, 132.0, 130.8, 130.2, 128.0,
127.8, 84.1, 75.3, 43.1, 16.3. HPLC conditions: Daicel Chiralpak
AD-H, i-PrOH/hexane 2:98, flow rate 0.5 mL/min, UV detection at
208 nm, tmajor (2R,3R) = 45.1 min, tminor (2S,3S) = 47.9 min.
Q-6 was prepared from O-benzoylquinine according to the liter-
ature procedure; white solid, 70% yield. 1H NMR (400 MHz, CDCl3):
d 8.66 (d, J = 4.5 Hz, 1H), 8.11 (d, J = 7.1 Hz, 1H), 8.00 (d, J = 9.1 Hz,
1H), 7.72 (d, J = 2.5 Hz, 1H), 7.61 (t, J = 7.4 Hz, 1H), 7.49 (t,
J = 7.7 Hz, 2H), 7.36 (d, J = 4.5 Hz, 1H), 7.31 (dd, J = 2.5, 9.1 Hz,
1H), 6.87 (d, J = 4.0 Hz, 1H), 5.75 (ddd, J = 7.5, 10.3, 17.4 Hz, 1H),
5.02–4.92 (m, 2H), 3.44–3.34 (m, 1H), 3.30–3.20 (m, 1H), 3.13
(dd, J = 10.3, 13.7 Hz, 2H), 2.78–2.62 (m, 3H), 2.38–2.28 (m, 1H),
1.96–1.90 (m, 2H), 1.86–1.71 (m, 2H), 1.66–1.56 (m, 1H).
4.3.4. (2R,3R)-1,3-Dinitro-2-(3-chlorophenyl)butane 10ad12
½
a 2D0
ꢂ
¼ þ8:0 (c 0.20, CH2Cl2). 1H NMR (400 MHz, CDCl3): d 7.32–
7.30 (m, 2H), 7.17 (s, 1H), 7.05 (d, J = 7.3 Hz, 1H), 4.96–4.88 (m, 2H),
4.83–4.80 (m, 1H), 4.01 (dd, J = 6.4, 14.5 Hz, 1H), 1.60 (d, J = 6.8 Hz,
3H). 13C NMR (100 MHz, CDCl3): d 135.7, 135.1, 130.6, 129.4, 128.4,
126.0, 83.9, 75.8, 46.9, 16.8. HPLC conditions: Daicel Chiralpak AS-
H, i-PrOH/hexane 10:90, flow rate 1.0 mL/min, UV detection at
208 nm, tmajor (2R,3R) = 25.7 min, tminor (2S,3S) = 30.0 min.
4.2.6. (S)-1-Benzhydryl-3-(4-((S)-benzyloxy((2S,4S,5R)-5-
vinylquinuclidin-2-yl)methyl)quinolin-6-yl)thiourea QD-730
Under nitrogen at room temperature, O-benzyl-6-aminoquini-
dine31,32 (400 mg, 1 mmol) was dissolved in THF (10 mL),
after which 3,5-bis(trifluoromethyl)phenyl isothiocyanate (298 mg,
1.1 mmol) was added into the solvent, and stirred for 24 h. The
solvent was removed under reduced atmosphere and then puri-
fied by column chromatography (ethyl acetate/methanol/triethyl-
amine 80:1:1, V/V/V) to give QD-7 as a colorless solid (396 mg,
62% yield). 1H NMR (400 MHz, CDCl3): d 8.84 (d, J = 4.4 Hz,
1H), 8.18 (s, 1H), 8.11 (d, J = 9.0 Hz, 1H), 7.66 (d, J = 7.5 Hz,
1H), 7.42 (s, 1H), 7.23–7.34 (m, 15H), 6.79–6.89 (m, 2H), 5.86
(m, 1H), 5.03 (br s, 1H), 4.99 (s, 1H), 4.96 (d, J = 5.3 Hz, 1H),
4.31 (d, J = 11.6 Hz, 1H), 4.16 (d, J = 11.5 Hz, 1H), 3.74 (t,
J = 6.5 Hz, 1H), 3.09 (s, 1H), 3.00 (s, 1H), 2.69–2.77 (m, 2H),
2.54–2.62 (m, 1H), 1.93 (s, 1H), 1.81–1.88 (m, 1H), 1.73 (s,
1H), 1.43–1.47 (m, 3H). 13C NMR (100 MHz, CDCl3): d 180.6,
149.6, 146.4, 146.3, 141.0, 140.4, 137.5, 131.3, 128.8, 128.4,
127.9, 127.8, 127.7, 127.6, 126.9, 126.5, 114.6, 71.3, 68.0, 62.0,
60.1, 49.8, 39.9, 28.0, 26.3, 25.6. HRMS (ESI-TOF): m/z calcd for
4.3.5. (2R,3R)-1,3-Dinitro-2-(4-chlorophenyl)butane 10ae11
½
a 2D0
ꢂ
¼ þ10:2 (c 1.02, CH2Cl2). 1H NMR (400 MHz, CDCl3): d
7.37–7.32 (m, 2H), 7.10 (d, J = 8.5 Hz, 2H), 4.98–4.85 (m, 2H),
4.79 (dd, J = 8.5, 13.6 Hz, 1H), 4.00 (dt, J = 6.3, 8.2 Hz, 1H), 1.59 (d,
J = 6.7 Hz, 3H). 13C NMR (100 MHz, CDCl3): d 135.3, 131.9, 129.6,
129.3, 83.9, 76.0, 46.9, 16.8. HPLC conditions: Daicel Chiralcel
OD-H, i-PrOH/hexane 30:70, flow rate 0.8 mL/min, UV detection
at 208 nm, tmajor (2R,3R) = 15.7 min, tminor (2S,3S) = 26.9 min.
4.3.6. (2R,3R)-1,3-Dinitro-2-(2-fluorophenyl)butane 10af11
½
a 2D0
ꢂ
¼ þ20:2 (c 1.05, CH2Cl2). 1H NMR (400 MHz, CDCl3): d
7.35–7.32 (m, 1H), 7.13–7.10 (m, 3H), 5.08–5.04 (m, 1H), 4.94–
4.82 (m, 2H), 4.32 (dd, J = 7.2, 14.3 Hz, 1H), 1.62 (d, J = 6.7 Hz,
3H). 13C NMR (100 MHz, CDCl3): d 131.0, 130.9, 129.7, 129.6,
125.0, 120.9, 120.8, 116.4, 116.2, 83.3, 75.1, 42.1, 17.0. HPLC condi-
tions: Daicel Chiralcel OD-H, i-PrOH/hexane 20:80, flow rate
0.8 mL/min, UV detection at 208 nm, tmajor (2R,3R) = 17.3 min, tmi-
C
40H40N4OS [M+H]+ 625.3001; found: 625.3000.
(2S,3S) = 28.8 min.
nor
4.3. Typical procedure for the Michael addition reaction
4.3.7. (2R,3R)-1,3-Dinitro-2-(3-fluorophenyl)butane 10ag
Nitroethane 8a (2.2 mL, 30 mmol) was added to a vial contain-
ing catalyst QD-2 (7 mg, 0.02 mmol) and trans-b-nitrostyrene 9a
(149 mg, 1 mmol) at 30 °C. TLC analysis indicated the completion
of the reaction. The reaction mixture was concentrated under vac-
uum. The dr value was determined by 1H NMR analysis of the res-
idue, which was then purified by flash silica gel chromatography
(ethyl acetate/hexane = 1:20 to 1:10) to afford the adduct syn-
10aa (125 mg, 0.56 mmol) as a white solid and anti-10aa (62 mg,
0.28 mmol) as a clear oil in 85% total yield.
½
a 2D0
ꢂ
¼ þ20:0 (c 1.05, CH2Cl2). 1H NMR (400 MHz, CDCl3): d
7.40–7.34 (m, 1H), 7.09–6.93 (m, 3H), 4.87–4.78 (m, 2H), 4.70–
4.65(m, 1H), 4.07–4.01 (m, 1H), 1.44 (d, J = 6.8 Hz, 3H). 13C NMR
(100 MHz, CDCl3): d 164.1, 161.7, 136.1, 131.0, 123.7, 116.2,
115.3, 84.0, 75.9, 47.0, 16.8. Daicel Chiralpak AS-H, i-PrOH/hexane
10:90, flow rate 1.0 mL/min, UV detection at 208 nm, tmajor
(2R,3R) = 24.0 min, tminor (2S,3S) = 27.1 min.
4.3.8. (2R,3R)-1,3-Dinitro-2-(4-fluorophenyl)butane 10ah11
½
a 2D0
ꢂ
¼ þ7:3 (c 0.87, CH2Cl2). 1H NMR (400 MHz, CDCl3): d 7.16–
4.3.1. (2R,3R)-1,3-Dinitro-2-phenylbutane 10aa11
7.13 (m, 2H), 7.08–7.03 (m, 2H), 4.99–4.86 (m, 2H), 4.79 (dd, J = 8.4,
13.6 Hz, 1H), 4.01 (dd, J = 6.3, 14.5 Hz, 1H), 1.60 (d, J = 6.7 Hz, 3H).
13C NMR (100 MHz, CDCl3): d 129.8, 116.5, 116.3, 84.0, 76.2, 46.8,
16.8. HPLC conditions: Daicel Chiralcel OD-H, i-PrOH/hexane
30:70, flow rate 0.8 mL/min, UV detection at 208 nm, tmajor
(2R,3R) = 14.0 min, tminor (2S,3S) = 17.2 min.
½
a 2D0
ꢂ
¼ þ4:9 (c 0.8, CH2Cl2). 1H NMR (400 MHz, CDCl3): d 7.37–
7.32 (m, 3H), 7.17–7.14 (m, 2H), 5.00–4.90 (m, 2H), 4.84–4.79
(m, 1H), 4.05–4.00 (m, 1H), 1.58 (d, J = 6.8 Hz, 3H). 13C NMR
(100 MHz, CDCl3): d 133.5, 129.3, 129.1, 128.0, 84.0, 76.1, 47.4,
16.7. HPLC conditions: Daicel Chiralpak AS-H, i-PrOH/hexane

1652
Y.-Q. Deng et al. / Tetrahedron: Asymmetry 23 (2012) 1647–1652
4.3.9. (2R,3R)-1,3-Dinitro-2-(4-methylphenyl)butane 10ai11
4.3.15. (S)-1,3-Dinitro-3-methyl-2-phenylbutane 10ba11
½
a 2D0
ꢂ
¼ þ11:9 (c 1.27, CH2Cl2). 1H NMR (400 MHz, CDCl3): d 7.15
1H NMR (400 MHz, CDCl3): d 7.43–7.31 (m, 3H), 7.22–7.16 (m,
2H), 4.98 (dd, J = 11.1, 13.4 Hz, 1H), 4.83–4.77 (m, 1H), 4.15 (dd,
J = 4.0, 11.0 Hz, 1H), 1.59 (d, J = 8.1 Hz, 6H). 13C NMR (100 MHz,
CDCl3): d 133.6, 129.1, 129.0, 128.9, 89.6, 75.9, 51.6, 26.2, 23.0.
HPLC conditions: Daicel Chiralpak AD-H, i-PrOH/hexane 5:95, flow
rate 0.7 mL/min, UV detection at 208 nm, tminor (R) = 16.2 min, tma-
(d, J = 7.9 Hz, 2H), 7.03 (d, J = 8.1 Hz, 2H), 4.96–4.88 (m, 2H), 4.85–
4.75 (m, 1H), 3.97 (m, 1H), 2.32 (s, 3H), 1.57 (d, J = 6.7 Hz, 3H). 13
C
NMR (100 MHz, CDCl3): d 139.0, 130.3, 130.0, 127.8, 84.1, 76.2,
47.1, 21.0, 16.7. HPLC conditions: Daicel Chiralcel OD-H, i-PrOH/
hexane 30:70, flow rate 0.8 mL/min, UV detection at 208 nm, tmajor
(2R,3R) = 15.5 min, tminor (2S,3S) = 46.5 min.
(S) = 16.9 min.
jor
4.3.10. (2R,3R)-1,3-Dinitro-2-(4-methoxyphenyl)butane 10aj11
Acknowledgments
½
a 2D0
ꢂ
¼ þ16:8 (c 0.67, CH2Cl2). 1H NMR (400 MHz, CDCl3): d 7.08
(d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 5.00–4.87 (m, 2H), 4.82–
4.76 (m, 1H), 3.96 (dd, J = 6.6, 14.1 Hz, 1H), 3.79 (s, 3H), 1.58 (d,
J = 6.7 Hz, 3H). 13C NMR (100 MHz, CDCl3): d 160.0, 129.1, 125.1,
114.7, 84.1, 76.4, 55.2, 46.8, 16.7. HPLC conditions: Daicel Chiralcel
OD-H, i-PrOH/hexane 30:70, flow rate 0.8 mL/min, UV detection at
208 nm, tmajor (2R,3R) = 18.2 min, tminor (2S,3S) = 36.6 min.
This work was financially supported by the European Commis-
sion through the project FP7–201431 (CATAFLU.OR) and the Intro-
duction of Innovative R&D Team Program of Guangdong Province
(No. 2009010058).
References
4.3.11. (2R,3R)-1,3-Dinitro-2-(2-furyl)butane 10ak11
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½
a 2D0
ꢂ
¼ þ17:1 (c 0.87, CH2Cl2). 1H NMR (400 MHz, CDCl3): d 7.38
(s, 1H), 6.33 (s, 1H), 6.26 (d, J = 3.1 Hz, 1H), 4.98–4.79 (m, 3H),
4.25–4.20 (m, 1H), 1.60 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz,
CDCl3): d 147.0, 143.5, 110.7, 109.6, 82.4, 74.2, 41.2, 16.3. HPLC
conditions: Daicel Chiralcel OD-H, i-PrOH/hexane 5:95, flow rate
0.8 mL/min, UV detection at 208 nm, tmajor (2R,3R) = 40.6 min, tmi-
(2S,3S) = 42.7 min.
nor
4.3.12. (2R,3R)-1,3-Dinitro-2-(2-thienyl)butane 10al16
½
a 2D0
ꢂ
¼ þ20:2 (c 1.05, CH2Cl2). 1H NMR (400 MHz, CDCl3): d
7.30–7.27 (m, 1H), 6.98 (dd, J = 3.6, 5.1 Hz, 1H), 6.92 (d, J = 3.5 Hz,
1H), 4.98–4.91 (m, 2H), 4.84–4.79 (m, 1H), 4.34 (dt, J = 5.8,
7.9 Hz, 1H), 1.61 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): d
135.0, 127.5, 127.3, 126.3, 84.0, 42.7, 16.7. HPLC conditions: Daicel
Chiralcel OD-H, i-PrOH/hexane 25:75, flow rate 1.0 mL/min, UV
detection
at
208 nm,
tmajor
(2R,3R) = 15.3 min,
tminor
(2S,3S) = 26.2 min.
18. Ooi, T.; Takada, S.; Doda, K.; Maruoka, K. Angew. Chem., Int. Ed. 2006, 45, 7606–
7608.
19. Marcelli, T.; Hiemstra, H. Synthesis 2010, 1229–1279.
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Tetrahedron: Asymmetry 2010, 21, 1715–1721.
4.3.13. (3R,4R)-2-Methyl-4-nitro-3-(nitromethyl)pentane
10am15
½
a 2D0
ꢂ
¼ ꢁ2:1 (c 0.2, CH2Cl2). 1H NMR (400 MHz, CDCl3): d 4.79–
4.72 (m, 2H), 4.49–4.44 (m, 2H), 2.88–2.86 (m, 1H), 1.60 (m, 3H),
1.56 (m, 6H). HPLC conditions: Daicel Chiralcel OD-H, i-PrOH/hex-
ane 10:90, flow rate 0.4 mL/min, UV detection at 210 nm, tmajor
(3R,4R) = 27.1 min, tminor (3S,4S) = 26.1 min.
25. Hammar, P.; Marcelli, T.; Hiemstra, H.; Himoa, F. Adv. Synth. Catal. 2007, 349,
2537–2548.
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27. Kolb, H. C.; Andersson, P. G.; Sharpless, K. B. J. Am. Chem. Soc. 1994, 116, 1278–
1291.
4.3.14. ((3R,4R,E)-(4-Nitro-3-(nitromethyl)pent-1-enyl)benzene
10an15
½
a 2D0
ꢂ
¼ þ31:3 (c 0.4, CH2Cl2). 1H NMR (400 MHz, CDCl3): d 7.34–
28. Calter, M. A. J. Org. Chem. 1996, 61, 8006–8007.
29. Shi, M.; Lei, Z.-Y.; Zhao, M.-X.; Shi, J.-W. Tetrahedron Lett. 2007, 48, 5743–5746.
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7.30 (m, 5H), 6.67–6.60 (m, 1H), 5.94–5.86 (m, 1H), 4.84–4.72 (m,
2H), 4.61–4.55 (m, 1H), 3.60–3.49 (m, 1H), 1.64–1.62 (m, 3H). HPLC
conditions: Daicel Chiralcel OD-H, i-PrOH/hexane 10:90, flow rate
1.0 mL/min, UV detection at 235 nm, tmajor (3R,4R) = 32.8 min, tmi-
(3S,4S) = 66.5 min.
nor