Asymmetric triple cascade organocatalytic reaction in water: Construction of polyfunctional cyclohexene building blocks having multiple stereocenters

Article abstract of DOI:10.1016/j.tetasy.2011.11.023

An asymmetric triple cascade organocatalytic reaction was carried out in water, which led to the construction of polyfunctional cyclohexene building blocks with multiple stereocenters with good diastereoselectivity and excellent enantioselectivity. This a

Full text of DOI:10.1016/j.tetasy.2011.11.023

Tetrahedron: Asymmetry 22 (2011) 2018–2023
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Tetrahedron: Asymmetry
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Asymmetric triple cascade organocatalytic reaction in water: construction of
polyfunctional cyclohexene building blocks having multiple stereocenters
Yaomei Jia a, Zhifeng Mao a, Rui Wang a,b,
⇑
a Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Life Sciences, and State Key
Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
b State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An asymmetric triple cascade organocatalytic reaction was carried out in water, which led to the con-
struction of polyfunctional cyclohexene building blocks with multiple stereocenters with good diastere-
oselectivity and excellent enantioselectivity. This asymmetric triple cascade process was found to be
quite effective for various nitroalkenes, including those with aliphatic substituents.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 31 October 2011
Accepted 29 November 2011
Available online 11 January 2012
1. Introduction
S
S
Ph
5
Over the past few decades, reactions using water as the solvent
have received a great deal of attention.1 For example, several highly
diastereoselective and enantioselective aldol,2a–e Mannich,2f Diels–
Alder2g,h and Michael3 reactions have been successfully performed
in aqueous media. Recently, great progress has been made in the
area of organocatalysis.4 One of the most powerful organocatalytic
strategies is organocascade catalysis.5 However, only a few organo-
cascade reactions have been reported to be carried out in water.6 All
of them were catalyzed by chiral secondary amines, which activated
the substrate carbonyl through enamine formation. Another major
category of amine catalysis relies on the activation of carbonyl Mi-
chael acceptors via the formation of iminium species.7 However,
no success has been met in aqueous organocascade reactions.
Recently, Enders et al. have developed a very effective enantio-
selective catalytic triple cascade reaction comprising a linear alde-
Ph
OTMS
5
N
H
N
H
N
H
OTMS
OTMS
6
7
5
Scheme 1. Organocatalysts evaluated herein.
catalyst 5 (20 mol %). After stirring at room temperature for 48 h,
the reaction provided the desired adduct 4a and its epimer with
good diastereoselectivity and excellent enantioselectivity (Table 1,
entry 1). However, the yield was moderate. When we conducted
the reaction in brine3j or neat conditions, the yield was not in-
creased (Table 1, entries 2 and 3). Since it had been reported that
Brønsted acids could promote the formation of enamine and imin-
ium species, we conducted the reaction in the presence of benzoic
acid (Table 1, entry 4). We found that the yield was improved, and
hyde, a nitroalkene, and an
a,b-unsaturated aldehyde, which
provided cyclohexene derivatives with four stereogenic centers in
excellent stereoselectivities using diphenylprolinol silyl ether as
the organocatalyst in toluene.5j We recently found that this reaction
could also be performed in water. Herein, we report our results
(Scheme 1).
so several other acids were tested. Among them, Boc-D-Phg-OH
turned out to be the best choice with the yield of 4a improved to
25% (Table 1, entry 7).
Since Palomo et al. have recently reported that catalyst 63g could
effectively promote the Michael reaction of enals with nitromethane
in water, we tested this catalyst in this triple cascade reaction. How-
ever, it did not increase the yield (Table 1, entry 5). During the exper-
iment, we observed that the first Michael reaction of aldehyde 1a
with nitroalkene 2a was very fast in water, which gave adduct A in
high yield (Scheme2). But in thefollowing step, the Michael addition
2. Results and discussion
Initially, we carried out the three component reaction of linear
aldehyde 1a (1.2 equiv), nitroalkene 2a (1.0 equiv), and a,b-unsat-
urated aldehyde 3a (1.05 equiv) in 1 mL of water in the presence of
of A to a,b-unsaturated aldehyde 3a was much slower in water. In
order to improve the rate of reaction, we added some basic additives
such as NaHCO3 and NaOAc to the reaction mixture, but worse
⇑
Corresponding author.
E-mail address: wangrui@lzu.edu.cn (R. Wang).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.11.023

Y. Jia et al. / Tetrahedron: Asymmetry 22 (2011) 2018–2023
2019
O
R1
NO2
R
H2O
product 4
R2
2
R
1
N
H
OTMS
catalyst (S)-5, 6, 7
H2O
enamine catalysis
water
water
R
R
O
O
N
R1
R2
OTMS
R1
R2
A
C
R3
R
NO2
NO2
R
O
N
O
OTMS
R1
R2
catalyst (S)-5,6,7
water
water
R3
enamine catalysis
3
R3
iminium catalysis
NO2
B
Scheme 2. Proposed catalytic cycle of the triple cascade reaction in water.5j
Table 1
Table 2
Optimization of conditions for triple cascade reaction in watera
Scope of the triple cascade reaction in water
O
O
O
O
CHO
CHO
Ph
R1
R3
R1
R2
7 (20 mol%)
Boc-D-Phg-OH (20 mol%)
SDBS (10 mol%)
catalyst (20 mol%)
3
1
3a
1a
additive (20 mol%)
R3
Ph
Ph
H2O, 48 h
NO2
NO2
NO2
Ph
NO2
R2
H2O, 40°C, 48 h
4a
2a
2
4
a
Entry
Cat.
Additive
Yieldb (%)
drc
eed (%)
Entry
4
R1
Et
R2
R3
Yieldb (%) drc
eed (%)
1e
5
5
5
5
6
5
5
5
5
5
5
5
5
5
7
7
7
7
None
None
None
PhCO2H
PhCO2H
HClO4
16 (20)
11
12
19 (22)
15 (19)
<5
25 (28)
<5
81:19
78:22
80:20
85:15
80:20
nd
90:10
nd
nd
87:13
86:14
85:15
87:13
88:12
89:11
90:10
89:11
88:12
>99
nd
nd
>99
>99
nd
>99
>99
nd
>99
>99
>99
>99
>99
>99
>99
>99
>99
2e,f
3e,g
4e
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
4a
Ph
Ph
Ph
Ph
Ph
Ph
39 (44) 89:11 >99
28 (32) 89:11 >99
38 (44) 86:14 >99
25 (30) 84:16 >99
40 (49) 82:18 >99
50 (58) 86:14 >99
56 (67) 84:16 >99
52 (65) 80:20 >99
51 (63) 81:19 >99
53 (65) 81:19 >99
52 (65) 80:20 >99
47 (62) 76:24 >99
38 (49) 78:22 >99
50 (59) 85:15 >99
39 (50) 79:21 >99
49 (63) 78:22 >99
51 (66) 78:22 >99
18 (20) 89:11 >99
16 (18) 90:10 >99
4b
4c
4d
4e
4f
4g
4h
4i
Me
n-Pr Ph
Bn
5e
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2-ClC6H4
4-BrC6H4
2-Naphthyl Ph
3-MeOC6H4 Ph
2-Furyl
2-BrC6H4
4-ClC6H4
n-Butyl
6e
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Ph
7e
Boc-
D
-Phg-OH
2-ClC6H4
2-BrC6H4
H
3-CH3C6H4
2-MeOC6H4
Ph
8e
NaHCO3
NaOAc
9e
14
10
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
21 (24)
21 (24)
18 (21)
22 (24)
24 (27)
26 (29)
33 (37)
35 (39)
39 (44)
11h
12i
13j
14k
15k
16k
17l
18l,m
4j
4k
4l
Ph
4m i-Pr
4n
4o
4p
4q
i-Pr
i-Pr
i-Pr
i-Pr
Boc-
Boc-
Boc-
D
D
D
-Phg-OH
-Phg-OH
-Phg-OH
Ph
Ph
Ph
Ph
a
4re i-Pr
4se i-Pr
Reactions condition: 1 (1.2 equiv), 2 (1 equiv), and 3 (1.5 equiv).
Yield of the isolated, single, major diastereomer (in parenthesis: yield of both
(CH2)3OTBS Ph
b
diastereomers).
a
Reactions condition: 1 (1.2 equiv), 2 (1.0 equiv), and 3 (1.5 equiv).
Yield of the isolated, single, major diastereomer (in parenthesis: yield of both
c
Determined by 1H NMR analysis of the crude reaction mixture.
b
d
The ee value of the major diastereomer was determined by HPLC on a chiral
phase.
diastereomers).
c
Determined by 1H NMR analysis of the crude reaction mixture.
e
Reactions condition: 1 (1.2 equiv), 2 (1.0 equiv), and 3 (1.05 equiv).
The solvent was brine.
No solvent was added.
5 mol % of SLS were used.
5 mol % of CTAB were used.
5 mol % of SDS were used.
5 mol % of SDBS were used.
10 mol % of SDBS were used.
d
The ee value of the major diastereomer was determined by HPLC on a chiral
phase.
f
g
h
i
e
The reaction time is 72 h.
j
k
l
results were obtained (Table 1, entries 8 and 9). We supposed that
the moderate yield might be due to insufficient mixing of the
reagents in water. Kobayashi has demonstrated that the surfactant
has an important beneficial effect on organometallic catalytic
m
Reaction performed at 40 °C. SDS = sodium dodecyl sulfate; CTAB = cetyltri-
methylammonium bromide; SLS = sodium lauryl sulfonate; SDBS = sodium dodecyl
benzene sulfonate.

2020
Y. Jia et al. / Tetrahedron: Asymmetry 22 (2011) 2018–2023
reactions in water.1c We then added some surfactants to the reaction
mixture. The yield was improved when surfactant (SDBS) (5%) was
used as the second additive (Table 1, entry 14).
Finally, we used dithienylprolinol silyl ether 7 to catalyze the
reaction in water (Table 1, entry 17); it exhibited similar catalytic
ability to diphenylprolinol silyl ether 5. The yield of the triple cas-
cade reaction could be further improved to 44% when the reaction
was performed at 40 °C (Table 1, entry 18).
(m, 3H), 7.18 (dd, J = 3.6, 1.2 Hz, 1H), 7.33–7.35 (m, 2H) ppm; 13C
NMR (75 MHz, CDCl3): d 1.5, 25.6, 27.4, 47.0, 68.3, 80.2, 125.2,
125.4, 125.8, 126.1, 126.6, 126.7, 149.0, 149.8 ppm; IR (CHCl3):
2957, 2869, 1433, 1405, 1250, 1232, 1097, 1075, 1049, 880, 842,
756, 699 cmꢀ1; HRMS (ESI): C16H23NOS2Si+H, Calcd: 338.1063,
Found: 338.1068; ½a D20
¼ ꢀ29 (c 1.0, CHCl3).
ꢁ
4.3. Typical procedure for the triple cascade reaction
Under the optimized reaction conditions, we set out to examine
the scope of the domino reaction in water. As shown in Table 2,
not only linear aldehydes (Table 2, entries 1–4) but also a branched
aldehyde (Table 2, entry 5) could be successfully employed in the
reaction, affording products 4a–e in moderate to good yields and
with excellent enantioselectivities (ee: >99%). The branched alde-
hyde 1 gave a higher yield in water. Aromatic and heteroaromatic
nitroalkenes were good substrates in these domino reactions. Both
electron-withdrawing and -donating substituents were introduced
onto the aromatic ring without compromising the yields or enanti-
oselectivities of the reactions. When two aliphatic nitroalkenes were
tested as substrates, both of them were able to furnish adduct 4 in
moderate yield (Table 2, entries 18 and 19).
To a solution of catalyst (S)-7 (33.7 mg, 0.1 mmol), Boc-D-
Phg-OH (25.1 mg, 0.1 mmol), SDBS (17.4 mg, 0.05 mmol), and
nitroalkene 2 (0.5 mmol, 1.0 equiv) in water (1 mL) were added
subsequently under stirring aldehyde 1 (0.6 mmol, 1.2 equiv) and
a
,b-unsaturated aldehyde 3 (0.75 mmol, 1.5 equiv) at 0 °C. After
1 h, the solution was allowed to warm to 40 °C, and stirred until
complete conversion of the starting materials (48–72 h). The reac-
tion was then quenched by adding saturated NaHCO3, and the
resulting mixture was extracted with ethyl acetate. The combined
organic layers were dried over Na2SO4 and concentrated. Purifica-
tion by flash column chromatography (silica gel, ethyl acetate/
petroleum ether, 1:10) afforded adduct 4.
The residue R3 of component 3 was also examined. Aliphatic
and aromatic moieties were tolerated very well. The diastereose-
lectivity of the domino reaction was good, and the enantioselectiv-
ity was excellent. In all cases complete enantiocontrol was
obtained. The absolute configuration of the products was deter-
mined by comparison of the specific rotation with literature data.5j
4.3.1. (3S,4S,5R,6R)-3-Ethyl-5-nitro-4,6-diphenylcyclohex-1-
enecarbaldehyde 4a (major diastereomer)
This compound was obtained after purification by flash column
chromatography (silica gel, ethyl acetate/petroleum ether = 1:10)
as a colorless oil (65 mg, yield 39%). 1H NMR (300 MHz, CDCl3): d
1.06 (t, J = 7.5 Hz, 3H), 1.39–1.53 (m, 1H), 1.69–1.83 (m, 1H), 3.05
(dd, J = 10.5, 3.3 Hz, 1H), 3.29–3.36 (m, 1H), 4.46 (s, 1H), 4.88
(dd, J = 3.3, 1.8 Hz, 1H), 6.98–7.01 (m, 2H), 7.20–7.23 (m, 2H),
7.25–7.30 (m, 3H), 7.32–7.41 (m, 4H), 9.61 (s, 1H) ppm. 13C NMR
(75 MHz, CDCl3): d 10.7, 25.0, 38.1, 42.7, 42.9, 92.5, 127.7, 127.9,
127.9, 128.0, 129.0, 129.1, 137.2, 137.6, 138.7, 154.4, 192.0 ppm.
IR (CHCl3): 2965, 1689, 1649, 1549, 1495, 1454, 1368, 1166, 910,
769, 732, 701, 617 cmꢀ1. HRMS (ESI): C21H21NO3+NH4, Calcd:
3. Conclusion
In conclusion, we have developed a chemo-, diastereo-, and enan-
tioselective triple cascade reaction in water. This system contains
one acid additive, one surfactant additive, and a newly designed organ-
ocatalyst which makes the triple cascade organocatalytic reaction pro-
ceed smoothly in water. Applications of the above system to the
synthesis of more complex molecules are currently underway.
353.1860, Found: 353.1852. ½a D20
¼ ꢀ51 (c 1.0, CHCl3). The ee
ꢁ
was determined by HPLC on a chiral phase (Daicel OD-H, n-hex-
ane/iso-propanol = 90:10, 1.0 mL/min), tr(major) = 10.9 min, tr(mi-
nor) = 16.0 min, >99%.
4. Experimental
4.1. General
4.3.2. (3S,4S,5S,6R)-3-Ethyl-5-nitro-4,6-diphenylcyclohex-1-
enecarbaldehyde 4a0 (minor diastereomer)
Unless stated otherwise, all reactions were carried out in flame
dried glassware. Distilled water was used as solvent. Proton nuclear
magnetic resonance (1H NMR) spectra were recorded on 300 MHz
spectrometer in CDCl3 unless otherwise noted and carbon nuclear
magnetic resonance (13C NMR) spectra were recorded on 75 MHz
spectrometer in CDCl3 using tetramethylsilane (TMS) as internal
standard unless otherwise noted. Data are presented as follows:
chemical shift, integration, multiplicity (br = broad, s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet, cm = complex
multiplet), and coupling constant in Hertz (Hz). IR absorptions are
given in wavenumbers (cmꢀ1). Optical rotations were reported as
This compound was obtained after purification by flash column
chromatography (silica gel, ethyl acetate/petroleum ether = 1:7) as
a colorless oil. 1H NMR (300 MHz, CDCl3): d 1.08 (t, J = 7.5 Hz, 3H),
1.42–1.58 (m, 1H), 1.70–1.83 (m, 1H), 2.65–2.72 (m, 1H), 3.26 (dd,
J = 12.3, 10.2 Hz, 1H), 4.65 (d, J = 5.7 Hz, 1H), 5.28 (dd, J = 12.6,
6.0 Hz, 1H), 7.07–7.12 (m, 3H), 7.15–7.18 (m, 2H), 7.22–7.25 (m,
2H), 7.27–7.32 (m, 4H), 9.53 (s, 1H) ppm. 13C NMR (75 MHz,
CDCl3): d 10.8, 24.4, 42.5, 42.7, 45.6, 90.0, 127.7, 128.1, 128.4,
128.4, 128.7, 128.7, 135.2, 138.8, 139.3, 152.1, 191.1 ppm. IR
(CHCl3): 2962, 2923, 2852, 2254, 1691, 1647, 1554, 1495, 1458,
follows: ½a rDt
ꢁ
(c: g/100 mL, in solvent). Mass peaks are identified by
1369, 909, 735, 703, 650 cmꢀ1
.
MS (ESI): C21H21NO3,
M+H = 336.2. ½a 2D0
¼ ꢀ186 (c 1.0, CHCl3).
ꢁ
the corresponding m/z values. The ee values determination was car-
ried out using chiral high-performance liquid chromatography
(HPLC) with a Chiracel OD-H column. Catalyst 7 was prepared
according to the literature.8 All racemic samples were obtained
according to a general procedure by using racemic catalyst 5.
4.3.3. (3S,4S,5R,6R)-3-Methyl-5-nitro-4,6-diphenylcyclohex-1-
enecarbaldehyde 4b
This compound was obtained after purification by flash column
chromatography (silica gel, ethyl acetate/petroleum ether = 1:10) as
a colorless solid (44.4 mg, yield 28%). Mp: 121–123 °C. 1H NMR
(300 MHz, CDCl3): d 1.23 (d, J = 7.2 Hz, 3H), 2.90 (dd, J = 10.2, 3.3 Hz,
1H), 3.40–3.51 (m, 1H), 4.48 (s, 1H), 4.86 (dd, J = 3.3, 1.5 Hz, 1H),
6.99–7.02 (m, 2H), 7.20–7.23 (m, 3H), 7.26–7.42 (m, 6H), 9.60 (s,
1H) ppm. 13C NMR (75 MHz, CDCl3): d 18.7, 32.1, 43.1, 45.2, 92.3,
127.7, 127.9, 128.0, 128.1, 129.0, 129.2, 136.7, 137.1, 138.6, 156.1,
192.0 ppm. IR (CHCl3): 2968, 1689, 1650, 1548, 1495, 1453, 1367,
4.2. Characterization data for catalyst 7
4.2.1. (S)-2-(Dithiophen-2-yl(trimethylsilyloxy)methyl)
pyrrolidine
(2.4 g, 65%). 1H NMR (300 MHz, CDCl3): d 0.01 (s, 9H), 1.41–1.54
(m, 1H), 1.60–1.72 (m, 1H), 1.75–1.93 (m, 2H), 2.03 (s, 1H), 2.78–
2.85 (m, 1H), 2.91–2.99 (m, 1H), 4.06 (t, J = 7.2 Hz, 1H), 7.00–7.06

Y. Jia et al. / Tetrahedron: Asymmetry 22 (2011) 2018–2023
2021
1166, 912, 762, 732, 702, 615 cmꢀ1. HRMS (ESI): C20H19NO3+NH4,
3H), 1.78–1.88 (m, 1H), 3.06 (dd, J = 11.1, 3.3 Hz, 1H), 3.24 (dd,
J = 11.1, 2.4 Hz, 1H), 4.81 (s, 1H), 4.89 (d, J = 3.3 Hz, 1H), 6.96–
7.02 (m, 3H), 7.21–7.24 (m, 1H), 7.26–7.33 (m, 4H), 7.41 (d,
J = 1.5 Hz 1H), 7.49 (dd, J = 7.5, 1.5 Hz, 1H), 9.63 (s, 1H) ppm. 13C
NMR (75 MHz, CDCl3): d 17.1, 21.3, 27.9, 39.7, 41.9, 42.4, 90.0,
127.1, 127.6, 128.2, 128.6, 129.1, 129.3, 130.6, 134.3, 136.0,
137.1, 138.8, 152.9, 191.6 ppm. IR (CHCl3): 2961, 1689, 1650,
1549, 1469, 1369, 1160, 1042, 911, 764, 733, 702, 615 cmꢀ1. HRMS
Calcd: 339.1703, Found: 339.1711. ½a D20
¼ ꢀ56 (c 1.0, CHCl3). The ee
ꢁ
was determined by HPLC on a chiral phase (Daicel OD-H, n-hexane/
iso-propanol = 90:10, 1.0 mL/min,), tr(major) = 13.5 min, tr(mi-
nor) = 17.8 min, >99%.
4.3.4. (3S,4S,5R,6R)-5-Nitro-4,6-diphenyl-3-propylcyclohex-1-
enecarbaldehyde 4c
This compound was obtained after purification by flash column
chromatography (silica gel, ethyl acetate/petroleum ether = 1:10)
as a colorless oil (66.5 mg, yield 38%). 1H NMR (300 MHz, CDCl3): d
0.92 (t, J = 6.9 Hz, 3H), 1.37–1.66 (m, 4H), 3.04 (dd, J = 10.5, 3.6 Hz,
1H), 3.34–3.36 (m, 1H), 4.46 (s, 1H), 4.87 (dd, J = 3.3, 1.8 Hz, 1H),
6.98–7.01 (m, 2H), 7.20–7.23 (m, 2H), 7.25–7.30 (m, 3H), 7.32–
7.41 (m, 4H), 9.60 (s, 1H) ppm. 13C NMR (75 MHz, CDCl3): d 14.1,
19.6, 34.5, 36.8, 42.9, 43.3, 92.5, 127.8, 127.9, 128.1, 129.0, 129.2,
137.3, 137.3, 138.7, 154.6, 192.0 ppm. IR (CHCl3): 2960, 2931,
1689, 1650, 1549, 1495, 1453, 1367, 1165, 911, 767, 733,
701 cmꢀ1. HRMS (ESI): C22H23NO3+NH4, Calcd: 367.2016, Found:
(ESI): C22H22ClNO3+NH4, Calcd: 401.1626, Found: 401.1618.
½
a 2D0
ꢁ
¼ þ39 (c 1.0, CHCl3). The ee was determined by HPLC on a chi-
ral phase (Daicel OD-H, n-hexane/iso-propanol = 90:10, 1.0 mL/
min,), tr(major) = 9.0 min, tr(minor) = 13.6 min, >99%.
4.3.8. (3S,4S,5R,6S)-6-(2-Bromophenyl)-3-isopropyl-5-nitro-4-
phenylcyclohex-1-enecarbaldehyde 4g
This compound was obtained after purification by flash column
chromatography (silica gel, ethyl acetate/petroleum ether = 1:10)
as a white solid (119 mg, yield 56%). Mp: 153–155 °C. 1H NMR
(300 MHz, CDCl3): d 0.90 (d, J = 6.9 Hz, 3H), 1.21 (d, J = 6.9 Hz,
3H), 1.78–1.88 (m, 1H), 3.07 (dd, J = 11.4, 3.3 Hz, 1H), 3.21 (dd,
J = 11.4, 2.1 Hz, 1H), 4.79 (s, 1H), 4.87 (d, J = 3.0 Hz, 1H), 6.95–
7.02 (m, 3H), 7.17–7.23 (m, 1H), 7.25–7.34 (m, 4H), 7.41 (d,
J = 1.2 Hz 1H), 7.68 (dd, J = 7.8, 1.2 Hz, 1H), 9.62 (s, 1H) ppm. 13C
NMR (75 MHz, CDCl3): d 17.0, 21.2, 27.8, 41.8, 42.1, 42.4, 90.2,
125.1, 127.6, 127.7, 128.2, 128.7, 129.1, 129.5, 134.0, 137.0,
137.6, 139.0, 152.7, 191.6 ppm. IR (CHCl3): 2960, 1689, 1650,
1549, 1464, 1367, 1160, 1025, 910, 764, 735, 701, 614 cmꢀ1. HRMS
367.2021. ½a 2D0
¼ ꢀ36 (c 1.0, CHCl3). The ee was determined by HPLC
ꢁ
on a chiral phase (Daicel OD-H, n-hexane/iso-propanol = 90:10,
1.0 mL/min), tr(major) = 9.6 min, tr(minor) = 12.7 min, >99%.
4.3.5. (3S,4S,5R,6R)-3-Benzyl-5-nitro-4,6-diphenylcyclohex-1-
enecarbaldehyde 4d
This compound was obtained after purification by flash column
chromatography (silica gel, ethyl acetate/petroleum ether = 1:10)
as a colorless solid (49.2 mg, yield 25%). Mp: 173–175 °C. 1H
NMR (300 MHz, CDCl3): d 2.68 (dd, J = 13.5, 7.2 Hz, 1H), 3.05–
3.17 (m, 2H), 3.74–3.80 (m, 1H), 4.37 (s, 1H), 4.79 (dd, J = 3.3,
1.2 Hz, 1H), 6.70–6.73 (m, 2H), 7.08–7.17 (m, 5H), 7.18–7.25 (m,
2H), 7.29–7.39 (m, 7H), 9.54 (s, 1H) ppm. 13C NMR (75 MHz,
CDCl3): d 37.5, 38.3, 41.6, 42.9, 92.6, 127.1, 127.7, 127.8, 128.0,
128.2, 128.7, 129.1, 129.3, 129.6, 136.9, 137.1, 137.9, 138.5,
153.8, 191.7 ppm. IR (CHCl3): 3029, 1688, 1650, 1548, 1494,
(ESI):
C22H22BrNO3+NH4, Calcd: 445.1121, Found: 445.1129.
½
a 2D0
ꢁ
¼ þ51 (c 1.0, CHCl3). The ee was determined by HPLC on a chi-
ral phase (Daicel OD-H, n-hexane/iso-propanol = 95:5, 1.0 mL/
min,), tr(major) = 11.2 min, tr(minor) = 18.5 min, >99%.
4.3.9. (3S,4S,5S)-3-Isopropyl-5-nitro-4-phenylcyclohex-1-ene
carbaldehyde 4h
This compound was obtained after purification by flash column
chromatography (silica gel, ethyl acetate/petroleum ether = 1:10) as
a colorless oil (71.1 mg, yield 52%). 1H NMR (300 MHz, CDCl3): d 0.91
(d, J = 6.9 Hz, 3H), 1.14 (d, J = 6.9 Hz, 3H), 1.84–1.94 (m, 1H), 2.82–
2.83 (m, 2H), 3.01–3.03 (m, 1H), 3.41 (dd, J = 6.9, 4.2 Hz, 1H), 4.91
(dd, J = 9.9, 5.7 Hz, 1H), 7.03–7.09 (m, 3H), 7.31–7.34 (m, 3H), 9.61 (s,
1H) ppm. 13C NMR (75 MHz, CDCl3): d 18.2, 21.0, 24.2, 30.2, 45.3,
45.6, 84.3, 127.7, 128.1, 129.1, 137.6, 137.7, 150.8, 192.3 ppm. IR
(CHCl3): 2961, 2929, 2873, 1722, 1684, 1647, 1548, 1495, 1457,
1371, 1163, 760, 702, 665 cmꢀ1. MS (ESI): C16H19NO3, M+H = 274.2.
1452, 1367, 1157, 1033, 911, 732, 702 cmꢀ1
C
(c 1.0, CHCl3). The ee was determined by HPLC on a chiral phase
(Daicel OD-H, n-hexane/iso-propanol = 70:30, 1.0 mL/min,), tr(ma-
jor) = 7.7 min, tr(minor) = 19.8 min, >99%.
. HRMS (ESI):
26H23NO3+NH4, Calcd: 415.2016, Found: 415.2012. ½a D20
¼ ꢀ16
ꢁ
4.3.6. (3S,4S,5R,6R)-3-Isopropyl-5-nitro-4,6-diphenylcyclohex-
1-enecarbaldehyde 4e
This compound was obtained after purification by flash column
chromatography (silica gel, ethyl acetate/petroleum ether = 1:10)
as a colorless solid (69.3 mg, yield 40%). Mp: 142–145 °C. 1H
½
a 2D0
ꢁ
¼ þ101 (c 1.0, CHCl3). The ee was determined by HPLC on a chiral
phase (Daicel OD-H, n-hexane/iso-propanol = 90:10, 1.0 mL/min,),
NMR (300 MHz, CDCl3):
d 0.91 (d, J = 6.9 Hz, 3H), 1.21 (d,
tr(major) = 15.6 min, tr(minor) = 18.2 min, >99%.
J = 6.9 Hz, 3H), 1.80–1.90 (m, 1H), 3.15 (dd, J = 11.1, 3.3 Hz, 1H),
3.31 (ddd, J = 11.1, 4.5, 2.7 Hz, 1H), 4.45 (s, 1H), 4.91 (dd, J = 3.3,
1.5 Hz, 1H), 6.97–7.00 (m, 2H), 7.21–7.23 (m, 2H), 7.25–7.30 (m,
3H), 7.32–7.41 (m, 4H), 9.63 (s, 1H) ppm. 13C NMR (75 MHz,
CDCl3): d 17.3, 21.3, 28.1, 41.4, 42.7, 42.8, 92.9, 127.7, 127.9,
127.9, 128.1, 129.1, 129.1, 137.3, 138.9, 138.9, 152.3, 191.9 ppm.
IR (CHCl3): 3030, 2961, 1689, 1647, 1549, 1494, 1454, 1368,
1159, 911, 767, 732, 701 cmꢀ1. HRMS (ESI): C22H23NO3+NH4,
4.3.10. (3S,4S,5R,6R)-3-Isopropyl-5-nitro-4-phenyl-6-m-tolyl
cyclohex-1-enecarbaldehyde 4i
This compound was obtained after purification by flash column
chromatography (silica gel, ethyl acetate/petroleum ether = 1:10)
as a white solid (92.8 mg, yield 51%). Mp: 50–52 °C. 1H NMR
(300 MHz, CDCl3): d 0.91 (d, J = 6.9 Hz, 3H), 1.14 (d, J = 6.9 Hz, 3H),
1.80–1.90 (m, 1H), 2.35 (s, 3H), 3.15 (dd, J = 10.8, 3.3 Hz, 1H), 3.28–
3.33 (m, 1H), 4.41 (s, 1H), 4.89 (dd, J = 3.3, 1.2 Hz, 1H), 6.97–7.01
(m, 3H), 7.05 (s, 1H), 7.11–7.16 (m, 1H), 7.22–7.32 (m, 4H), 7.34 (d,
J = 2.4 Hz, 1H), 9.62 (s, 1H) ppm. 13C NMR (75 MHz, CDCl3): d 17.2,
21.3, 21.4, 28.1, 41.4, 42.7, 42.8, 93.0, 124.7, 127.7, 128.0, 128.7,
128.9, 128.9, 129.1, 137.4, 138.8, 138.9, 139.0, 152.1, 191.9 ppm.
IR (CHCl3): 2961, 2928, 1689, 1647, 1549, 1492, 1457, 1368, 1159,
911, 787, 733, 702 cmꢀ1. HRMS (ESI): C23H25NO3+NH4, Calcd:
Calcd: 367.2016, Found: 367.2013. ½a D20
¼ ꢀ47 (c 1.0, CHCl3). The
ꢁ
ee was determined by HPLC on a chiral phase (Daicel OD-H, n-hex-
ane/iso-propanol = 90:10, 1.0 mL/min), tr(major) = 9.5 min, tr(mi-
nor) = 14.7 min, >99%.
4.3.7. (3S,4S,5R,6S)-6-(2-Chlorophenyl)-3-isopropyl-5-nitro-4-
phenylcyclohex-1-enecarbaldehyde 4f
This compound was obtained after purification by flash column
chromatography (silica gel, ethyl acetate/petroleum ether = 1:10)
as a white solid (95.2 mg, yield 50%). Mp: 145–148 °C. 1H NMR
(300 MHz, CDCl3): d 0.90 (d, J = 6.9 Hz, 3H), 1.21 (d, J = 6.9 Hz,
381.2173, Found: 381.2176. ½a D20
¼ ꢀ51 (c 1.0, CHCl3). The ee was
ꢁ
determined by HPLC on a chiral phase (Daicel OD-H, n-hexane/
iso-propanol = 90:10, 1.0 mL/min), tr(major) = 7.3 min, tr(mi-
nor) = 13.7 min, >99%.

2022
Y. Jia et al. / Tetrahedron: Asymmetry 22 (2011) 2018–2023
4.3.11. (3S,4S,5R,6R)-3-Isopropyl-6-(2-methoxyphenyl)-5-nitro-
4-phenylcyclohex-1-enecarbaldehyde 4j
21.3, 28.2, 41.6, 42.8, 42.9, 92.8, 125.2, 126.3, 126.4, 127.0, 127.6,
127.7, 128.0, 129.0, 129.2, 132.9, 133.4, 134.7, 138.9, 139.0,
152.2, 191.9 ppm. IR (CHCl3): 2960, 2929, 1689, 1648, 1548,
1456, 1365, 1161, 909, 820, 733, 703 cmꢀ1. MS (ESI): C26H25NO3,
This compound was obtained after purification by flash column
chromatography (silica gel, ethyl acetate/petroleum ether = 1:10)
as a white solid (100.2 mg, yield 53%). Mp: 177–179 °C. 1H NMR
(300 MHz, CDCl3): d 0.88 (d, J = 6.9 Hz, 3H), 1.19 (d, J = 6.9 Hz,
3H), 1.74–1.85 (m, 1H), 3.06 (dd, J = 11.4, 3.6 Hz, 1H), 3.18–3.23
(m, 1H), 3.87 (s, 3H), 4.77 (s, 1H), 4.87 (d, J = 3 Hz, 1H), 6.87–6.99
(m, 5H), 7.26–7.37 (m, 5H), 9.63 (s, 1H) ppm. 13C NMR (75 MHz,
CDCl3): d 17.1, 21.3, 27.9, 36.8, 42.1, 42.6, 55.5, 90.4, 110.8,
120.4, 126.7, 127.7, 127.9, 128.0, 129.0, 129.2, 137.7, 139.3,
152.6, 156.5, 192.0 ppm. IR (CHCl3): 2960, 2931, 1689, 1548,
1491, 1461, 1368, 1247, 1160, 1028, 758, 701 cmꢀ1. HRMS (ESI):
M+H = 400.2. ½a 2D0
¼ ꢀ40 (c 1.0, CHCl3). The ee was determined
ꢁ
by HPLC on a chiral phase (Daicel OD-H, n-hexane/iso-propa-
nol = 90:10, 1.0 mL/min), tr(major) = 11.4 min, tr(minor) = 17.3 -
min, >99%.
4.3.15. (3S,4S,5R,6R)-3-Isopropyl-4-(3-methoxyphenyl)-5-nitro-
6-phenylcyclohex-1-enecarbaldehyde 4n
This compound was obtained after purification by flash column
chromatography (silica gel, ethyl acetate/petroleum ether = 1:10)
as a white solid (95.0 mg, yield 50%). Mp: 46–48 °C. 1H NMR
(300 MHz, CDCl3): d 0.91 (d, J = 6.9 Hz, 3H), 1.21 (d, J = 6.9 Hz,
3H), 1.82–1.92 (m, 1H), 3.11 (dd, J = 11.1, 3.3 Hz, 1H), 3.28 (dd,
J = 10.8, 1.8 Hz, 1H), 3.74 (s, 3H), 4.44 (s, 1H), 4.90 (dd, J = 3.3,
1.2 Hz, 1H), 6.51–6.52 (m, 1H), 6.58 (d, J = 7.8 Hz, 1H), 6.80 (dd,
J = 8.1, 2.1 Hz, 1H), 7.18–7.23 (m, 3H), 7.29–7.40 (m, 4H), 9.26 (s,
1H) ppm. 13C NMR (75 MHz, CDCl3): d 17.3, 21.3, 28.1, 41.4, 42.8,
42.8, 55.2, 92.8, 112.5, 114.2, 119.8, 127.9, 127.9, 129.1, 130.1,
138.8, 138.9, 138.9, 152.2, 159.9, 191.9 ppm. IR (CHCl3): 2960,
1689, 1604, 1588, 1549, 1491, 1456, 1367, 1267, 1160, 1048,
C23H25NO4+NH4, Calcd: 397.2122, Found: 397.2115. ½a D20
¼ þ43
ꢁ
(c 1.0, CHCl3). The ee was determined by HPLC on a chiral phase
(Daicel OD-H, n-hexane/iso-propanol = 90:10, 1.0 mL/min,), tr(ma-
jor) = 7.8 min, tr(minor) = 11.2 min, >99%.
4.3.12. (3S,4S,5R,6R)-4-(2-Chlorophenyl)-3-isopropyl-5-nitro-6-
phenylcyclohex-1-enecarbaldehyde 4k
This compound was obtained after purification by flash column
chromatography (silica gel, ethyl acetate/petroleum ether = 1:10)
as a white solid (99.8 mg, yield 52%). Mp: 108–110 °C. 1H NMR
(300 MHz, CDCl3): d 0.90 (d, J = 6.9 Hz, 3H), 1.22 (d, J = 7.2 Hz,
3H), 1.76–1.86 (m, 1H), 3.30 (dd, J = 11.4, 1.8 Hz, 1H), 3.86 (dd,
J = 11.4, 3.0 Hz, 1H), 4.52 (s, 1H), 4.92 (d, J = 2.4 Hz, 1H), 7.13–
7.18 (m, 1H), 7.20–7.28 (m, 4H), 7.30–7.40 (m, 5H), 9.65 (s,
1H) ppm. 13C NMR (75 MHz, CDCl3): d 17.4, 21.2, 28.1, 36.9, 42.0,
43.0, 90.4, 127.4, 127.8, 127.9, 127.9, 129.0, 129.1, 130.2, 134.3,
134.5, 138.3, 139.1, 151.7, 191.8 ppm. IR (CHCl3): 2961, 1689,
1646, 1548, 1473, 1449, 1368, 1162, 1035, 911, 763, 734,
703 cmꢀ1. HRMS (ESI): C22H22ClNO3+NH4, Calcd: 401.1626, Found:
911, 732, 701 cmꢀ1
.
HRMS (ESI): C23H25NO4+NH4, Calcd:
397.2122, Found: 397.2130. ½a D20
¼ ꢀ32 (c 1.0, CHCl3). The ee
ꢁ
was determined by HPLC on a chiral phase (Daicel OD-H, n-hex-
ane/iso-propanol = 90:10, 1.0 mL/min), tr(major) = 11.0 min, tr(mi-
nor) = 16.8 min, >99%.
4.3.16. (3S,4R,5S,6R)-4-(Furan-2-yl)-3-isopropyl-5-nitro-6-
phenylcyclohex-1-enecarbaldehyde 4o
This compound was obtained after purification by flash column
chromatography (silica gel, ethyl acetate/petroleum ether = 1:10)
as a white solid (65.7 mg, yield 39%). Mp: 131–133 °C. 1H NMR
(300 MHz, CDCl3): d 0.95 (d, J = 6.9 Hz, 3H), 1.24 (d, J = 7.2 Hz,
3H), 1.95–2.06 (m, 1H), 3.17 (ddd, J = 10.5, 4.8, 3.0 Hz, 1H),3.32
(dd, J = 10.5, 3.6 Hz, 1H), 4.48 (s, 1H), 5.05 (dd, J = 3.6, 2.1 Hz,
1H), 6.10 (d, J = 3.3 Hz, 1H), 6.30 (dd, J = 3.3, 1.8 Hz, 1H), 7.19–
7.22 (m, 2H), 7.27–7.35 (m, 4H), 7.38–7.40 (m, 1H), 9.60 (s,
1H) ppm. 13C NMR (75 MHz, CDCl3): d 17.8, 21.3, 28.9, 35.6, 42.2,
42.9, 90.3, 107.7, 110.5, 127.9, 127.9, 129.2, 138.4, 138.8, 142.3,
151.2, 151.4, 191.7 ppm. IR (CHCl3): 2961, 1690, 1649, 1551,
1499, 1456, 1366, 1157, 1014, 912, 736, 703 cmꢀ1. HRMS (ESI):
401.1621. ½a 2D0
ꢁ
¼ þ35 (c 1.0, CHCl3). The ee was determined by
HPLC on
a chiral phase (Daicel OD-H, n-hexane/iso-propa-
nol = 90:10, 1.0 mL/min,), tr(major) = 11.5 min, tr(minor) = 19.1 -
min, >99%.
4.3.13. (3S,4S,5R,6R)-4-(4-Bromophenyl)-3-isopropyl-5-nitro-6-
phenylcyclohex-1-enecarbaldehyde 4l
This compound was obtained after purification by flash column
chromatography (silica gel, ethyl acetate/petroleum ether = 1:10)
as a white solid (99.6 mg, yield 47%). Mp: 57–59 °C. 1H NMR
(300 MHz, CDCl3): d 0.90 (d, J = 6.9 Hz, 3H), 1.21 (d, J = 7.2 Hz,
3H), 1.77–1.87 (m, 1H), 3.12 (dd, J = 11.1, 3.3 Hz, 1H), 3.24 (ddd,
J = 11.1, 4.2, 2.4 Hz, 1H), 4.45 (s, 1H), 4.86 (dd, J = 3.3, 1.2 Hz, 1H),
6.87 (d, J = 8.4 Hz, 2H), 7.19–7.22 (m, 2H), 7.29–7.36 (m, 3H),
7.37–7.43 (m, 3H), 9.62 (s, 1H) ppm. 13C NMR (75 MHz, CDCl3): d
17.3, 21.3, 28.2, 41.0, 42.7, 42.8, 92.6, 122.1, 127.9, 128.0, 129.2,
129.5, 132.3, 136.4, 138.7, 138.9, 151.6, 191.7 ppm. IR (CHCl3):
2961, 1689, 1648, 1549, 1490, 1456, 1367, 1158, 1075, 1009,
C
20H21NO4+NH4, Calcd: 357.1809, Found: 357.1818. ½a D20
¼ ꢀ73
ꢁ
(c 1.0, CHCl3). The ee was determined by HPLC on a chiral phase
(Daicel OD-H, n-hexane/iso-propanol = 90:10, 1.0 mL/min), tr(ma-
jor) = 10.3 min, tr(minor) = 14.8 min, >99%.
4.3.17. (3S,4S,5R,6R)-4-(2-Bromophenyl)-3-isopropyl-5-nitro-6-
phenylcyclohex-1-enecarbaldehyde 4p
910, 733, 703 cmꢀ1
.
HRMS (ESI): C22H22BrNO3+NH4, Calcd:
This compound was obtained after purification by flash column
chromatography (silica gel, ethyl acetate/petroleum ether = 1:10)
as a white solid (104.8 mg, yield 49%). Mp: 127–129 °C. 1H NMR
(300 MHz, CDCl3): d 0.91 (d, J = 6.9 Hz, 3H), 1.21 (d, J = 7.2 Hz,
3H), 1.74–1.84 (m, 1H), 3.29 (dd, J = 11.4, 2.1 Hz, 1H), 3.82 (dd,
J = 11.4, 3.3 Hz, 1H), 4.51 (s, 1H), 4.91 (d, J = 2.4 Hz, 1H), 7.10–
7.16 (m, 2H), 7.24–7.28 (m, 3H), 7.29–7.32 (m, 1H), 7.34–7.40
(m, 3H), 7.48–7.52 (m, 1H), 9.65 (s, 1H) ppm. 13C NMR (75 MHz,
CDCl3): d 17.5, 21.2, 28.1, 39.8, 42.2, 43.0, 90.5, 125.4, 127.9,
128.0, 128.1, 129.0, 129.4, 133.6, 135.8, 138.2, 139.0, 151.7,
191.9 ppm. IR (CHCl3): 2961, 2929, 1689, 1647, 1548, 1469,
445.1121, Found: 445.1116. ½a D20
¼ ꢀ58 (c 1.0, CHCl3). The ee
ꢁ
was determined by HPLC on a chiral phase (Daicel OD-H, n-hex-
ane/iso-propanol = 90:10, 1.0 mL/min,), tr(major) = 10.5 min, tr(mi-
nor) = 16.0 min, >99%.
4.3.14. (3S,4S,5R,6R)-3-Isopropyl-4-(naphthalen-2-yl)-5-nitro-6-
phenylcyclohex-1-enecarbaldehyde 4m
This compound was obtained after purification by flash column
chromatography (silica gel, ethyl acetate/petroleum ether = 1:10)
as a white solid (76.5 mg, yield 38%). Mp: 69–71 °C. 1H NMR
(300 MHz, CDCl3): d 0.92 (d, J = 6.9 Hz, 3H), 1.22 (d, J = 6.9 Hz,
3H), 1.83–1.93 (m, 1H), 3.32 (dd, J = 11.1, 3.3 Hz, 1H), 3.41–3.46
(m, 1H), 4.49 (s, 1H), 5.00 (dd, J = 3.0, 1.2 Hz, 1H), 7.08 (dd,
J = 8.7, 1.8 Hz, 1H), 7.24–7.27 (m, 2H), 7.32–7.48 (m, 7H), 7.70–
7.82 (m, 3H), 9.65 (s, 1H) ppm. 13C NMR (75 MHz, CDCl3): d 17.3,
1368, 1161, 1024, 910, 764, 733, 702 cmꢀ1
C
(c 1.0, CHCl3). The ee was determined by HPLC on a chiral phase
(Daicel OD-H, n-hexane/iso-propanol = 90:10, 1.0 mL/min), tr(ma-
jor) = 11.8 min, tr(minor) = 22.4 min, >99%.
. HRMS (ESI):
22H22BrNO3+NH4, Calcd: 445.1121, Found: 445.1132. ½a D20
¼ þ52
ꢁ

Y. Jia et al. / Tetrahedron: Asymmetry 22 (2011) 2018–2023
2023
4.3.18. (3S,4S,5R,6R)-4-(4-Chlorophenyl)-3-isopropyl-5-nitro-6-
phenylcyclohex-1-enecarbaldehyde 4q
National S & T Program ‘Major New Drug Development’ of the Min-
istry of Science and Technology (2012ZX09504001-003).
This compound was obtained after purification by flash column
chromatography (silica gel, ethyl acetate/petroleum ether = 1:10)
as a white solid (96.9 mg, yield 51%). Mp: 61–63 °C. 1H NMR
(300 MHz, CDCl3): d 0.90 (d, J = 6.9 Hz, 3H), 1.21 (d, J = 7.2 Hz,
3H), 1.77–1.87 (m, 1H), 3.12 (dd, J = 11.1, 3.3 Hz, 1H), 3.24 (ddd,
J = 11.1, 4.5, 2.7 Hz, 1H), 4.45 (s, 1H), 4.86 (dd, J = 3.3, 1.2 Hz, 1H),
6.87 (d, J = 8.4 Hz, 2H),7.19–7.22 (m, 2H), 7.30–7.36 (m, 3H),
7.38–7.43 (m, 3H), 9.62 (s, 1H) ppm. 13C NMR (75 MHz, CDCl3): d
17.3, 21.3, 28.1, 41.0, 42.7, 42.7, 92.6, 122.1, 127.9, 128.0, 129.2,
129.5, 132.3, 136.4, 138.7, 138.9, 151.7, 191.7 ppm. IR (CHCl3):
2960, 1689, 1648, 1548, 1490, 1456, 1367, 1158, 1075, 1009,
References
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Luo, S.; Mi, X.; Liu, S.; Xu, H.; Cheng, J.-P. Chem. Commun. 2006, 3687; (d)
Carlone, A.; Marigo, M.; North, C.; Landa, A.; Jørgensen, K. A. Chem. Commun.
2006, 4928; (e) Zhu, S.; Yu, S.; Ma, D. Angew. Chem., Int. Ed. 2008, 47, 545; (f)
Palomo, C.; Landa, A.; Mielgo, A.; Oiarbide, M.; Puente, À.; Vera, S. Angew. Chem.,
Int. Ed. 2007, 46, 8431; (g) Wang, J.; Yu, F.; Zhang, X.; Ma, D. Org. Lett. 2008, 10,
2561; (h) Zheng, Z.; Perkins, B. L.; Ni, B. J. Am. Chem. Soc. 2010, 132, 50; (i) Mao,
Z.; Jia, Y.; Li, W.; Wang, R. J. Org. Chem. 2010, 75, 7428; (j) Bae, H. Y.; Some, S.; Oh,
J. S.; Lee, Y. S.; Song, C. E. Chem. Commun. 2011, 9621; For a recent review: (k)
Raj, M.; Singh, V. K. Chem. Commun. 2009, 6687.
733, 703 cmꢀ1. MS (ESI): C22H22ClNO3, M+H = 384.2. ½a D20
¼ ꢀ58
ꢁ
(c 1.0, CHCl3). The ee was determined by HPLC on a chiral phase
(Daicel OD-H, n-hexane/iso-propanol = 90:10, 1.0 mL/min), tr(ma-
jor) = 10.6 min, tr(minor) = 16.1 min, >99%.
4.3.19. (3S,4R,5R,6R)-4-Butyl-3-isopropyl-5-nitro-6-phenylcyclo
hex-1-enecarbaldehyde 4r
This compound was obtained after purification by flash column
chromatography (silica gel, ethyl acetate/petroleum ether = 1:10)
as a colorless oil (30.4 mg, yield 18%). 1H NMR (300 MHz, CDCl3):
d 0.85 (t, J = 6.6 Hz, 3H), 1.06 (d, J = 6.9 Hz, 3H), 1.20–1.29 (m,
6H), 1.39–1.55 (m, 3H), 2.22–2.45 (m, 3H), 4.48 (d, J = 5.4 Hz,
1H), 4.89 (dd, J = 11.7, 6.3 Hz, 1H), 7.03 (d, J = 6.6 Hz, 3H), 7.27–
7.29 (m, 3H), 9.47 (s, 1H) ppm. 13C NMR (75 MHz, CDCl3): d 13.9,
17.4, 21.9, 23.1, 27.0, 27.4, 28.1, 32.7, 42.4, 46.1, 89.7, 128.2,
128.4, 128.5, 135.8, 140.3, 150.3, 191.1 ppm. IR (CHCl3): 2960,
2930, 2871, 1690, 1647, 1550, 1463, 1368, 1106, 910, 735,
4. For selected reviews on organocatalysis, see: Berkessel, A.; Gröger, H.
Asymmetric Organocatalysis: From Biomimetic Concepts to Applications in
Asymmetric Synthesis; Wiley-VCH: Weinheim, 2004; (b) List, B. Chem. Commun.
2006, 819; (c) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520;
(d) MacMillan, D. W. C. Nature 2008, 455, 304; (e) Barbas, C. F., III Angew. Chem.,
Int. Ed. 2008, 47, 42; (f) Bertelsen, S.; Jørgensen, K. A. Chem. Soc. Rev. 2009, 38,
2178.
701 cmꢀ1. MS (ESI): C20H27NO3, M+H = 330.3. ½a 2D0
¼ ꢀ175 (c 0.5,
ꢁ
CHCl3). The ee was determined by HPLC on a chiral phase (Daicel
OD-H,
n-hexane/iso-propanol = 80:20,
1.0 mL/min),
tr(ma-
5. For reviews on organocatalytic domino reactions, see: (a) Enders, D.; Grondal, C.;
Hüttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570; (b) Yu, X.; Wang, W. Org.
Biomol. Chem. 2008, 6, 2037; (c) Guo, H. C.; Ma, J. A. Angew. Chem., Int. Ed. 2006,
45, 354; (d) Walji, A. M.; MacMillan, D. W. C. Synlett 2007, 1477; (e) Nicolaou, K.
C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134; (f)
Pellissier, H. Tetrahedron 2006, 62, 1619; (g) Westermann, B.; Ayaz, M.; Berkel, S.
S. Angew. Chem., Int. Ed. 2010, 49, 846; For significant examples, see: (h) Huang,
Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127,
15051; (i) Marigo, M.; Schulte, T.; Franzen, J.; Jørgensen, K. A. J. Am. Chem. Soc.
2005, 127, 15710; (j) Enders, D.; Hüttl, M. R. M.; Grondal, C.; Raabe, G. Nature
2006, 441, 861; (k) Enders, D.; Hüttl, M. R. M.; Raabe, G.; Bats, J. W. Adv. Synth.
Catal. 2008, 350, 267; (l) Rueping, M.; Haack, K. L.; Ieawsuwan, W.; Sundén, H.;
Blanco, M.; Schoepke, F. R. Chem. Commun. 2011, 3828; (m) Urushima, T.;
Sakamoto, D.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2010, 12, 4588; (n) Ishikawa,
H.; Suzuki, T.; Hayashi, Y. Angew. Chem., Int. Ed. 2009, 48, 1304; (o) Ishikawa, H.;
Suzuki, T.; Orita, H.; Uchimaru, T.; Hayashi, Y. Chem. Eur. J. 2010, 16, 12616.
6. (a) Tan, B.; Zhu, D.; Zhang, L.; Chua, P. J.; Zeng, X.; Zhong, G. Chem. Eur. J. 2010,
16, 3842; (b) Scroggins, S. T.; Chi, Y.; Fréchet, J. M. J. Angew. Chem., Int. Ed. 2010,
49, 2393.
jor) = 8.8 min, tr(minor) = 19.3 min, >99%.
4.3.20. (3S,4R,5R,6R)-4-(3-(tert-butyldimethylsilyloxy)propyl)-
3-isopropyl-5-nitro-6-phenylcyclohex-1-enecarbaldehyde 4s
This compound was obtained after purification by flash column
chromatography (silica gel, ethyl acetate/petroleum ether = 1:10)
as a colorless oil (35.2 mg, yield 16%). 1H NMR (300 MHz, CDCl3):
d 0.00 (s, 6H), 0.86 (s, 9H), 1.06 (d, J = 6.9 Hz, 3H), 1.26 (d,
J = 6.9 Hz, 3H), 1.36–1.55 (m, 4H), 2.25–2.44 (m, 3H), 3.46–3.56
(m, 2H), 4.47 (d, J = 6.0 Hz, 1H), 4.88 (dd, J = 11.4, 6.0 Hz, 1H),
7.02 (d, J = 6.9 Hz, 3H), 7.26–7.28 (m, 3H), 9.47 (s, 1H) ppm. 13C
NMR (75 MHz, CDCl3): d ꢀ5.4, 17.4, 18.2, 21.8, 24.6, 25.8, 27.3,
28.1, 29.7, 32.5, 42.4, 46.2, 62.5, 89.7, 128.2, 128.4, 128.5, 135.7,
140.4, 150.2, 191.1 ppm. IR (CHCl3): 2956, 2929, 2856, 1691,
1551, 1466, 1366, 1254, 1101, 837, 777, 701, 663 cmꢀ1. MS (ESI):
7. For recent reviews on aminocatalysis, see: (a) Melchiorre, P.; Marigo, M.;
Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138; (b) Mukherjee, S.;
Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471; (c) Lelais, G.;
MacMillan, D. W. C. Aldrichim. Acta 2006, 39, 79.
8. Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44,
4212.
C
25H39NO4Si, M+H = 446.3. ½a D20
¼ ꢀ98 (c 1.0, CHCl3). The ee was
ꢁ
determined by HPLC on a chiral phase (Daicel OD-H, n-hexane/
iso-propanol = 80:20, 1.0 mL/min,), tr(major) = 7.3 min, tr(mi-
nor) = 14.8 min, >99%.
Acknowledgments
We are grateful for the grants from the National Natural Science
Foundation of China (Nos. 90813012 and 20932003), the Key