Highly enantioselective desymmetrization of meso- and prochiral cyclic ketones via organocatalytic Michael reaction

Article abstract of DOI:10.1016/j.tet.2009.09.005

An efficient and novel organocatalyst has been developed for the asymmetric desymmetrization of meso- and prochiral ketones by direct Michael addition to nitroolefins. This strategy can afford the desymmetrization products with excellent diastereo- (up to

Full text of DOI:10.1016/j.tet.2009.09.005

Tetrahedron 65 (2009) 9238–9243
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Highly enantioselective desymmetrization of meso- and prochiral cyclic ketones
via organocatalytic Michael reaction
*
Jia-Rong Chen, Yuan-Yuan Lai, Hai-Hua Lu, Xu-Fan Wang, Wen-Jing Xiao
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan, Hubei 430079, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 July 2009
Received in revised form 1 September 2009
Accepted 3 September 2009
Available online 6 September 2009
An efficient and novel organocatalyst has been developed for the asymmetric desymmetrization of meso-
and prochiral ketones by direct Michael addition to nitroolefins. This strategy can afford the de-
symmetrization products with excellent diastereo- (up to >99:1) and enantioselectivity (up to 96%) in
great yields (up to 95%).
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
nitro group through double hydrogen bonding interaction, these
bifunctional organocatalysts showed highly diastereo- and enan-
Asymmetric organocatalysis, the use of small chiral organic
molecules as catalysts, has become a field of central importance for
the stereoselective preparation of chiral, enantioenriched building
blocks.1 In particular, the use of chiral secondary amines exploiting
catalytic enamine,2 iminium ion,3 SOMO,4 and dienamine5 activa-
tion modes have proven to be a powerful protocol for stereo-
selective functionalization of carbonyl compounds. Among the
tioselectivity for the Michael reaction of cyclohexanone with
b
selectivity can be finely tuned by a simple modification of the
structural motif of the catalyst.
-nitrostyrenes (Eq. 1).15e–f Furthermore, we found that activity and
O
O
S
R1
N
H
HO
N
H
HO
N
H
N
H
R2
N
H
N
H
N
H
various
a-functionalizations of carbonyl compounds, the asym-
H-Bonding
H-Bonding
metric Michael reaction of carbonyl compounds to nitroolefins
represents an easy approach to the formation of synthetically
H-Bonding
1a:
R1= t-Bu
2a: R2= H
2b:
3
1b: R1=1-naphthyl
R2= 4-OCH3
2c: R2= 3, 5-(i-Pr)2
1c:
R1= 3,5-(CF3)2-phenyl
1d:
useful
g-nitrocarbonyl compounds, which serve as versatile in-
R1= Phenyl
1e: R1= c-Hex
termediates for the preparation of complex organic targets.6,7 Ac-
cordingly, considerable efforts have been directed toward the
development of organocatalytic systems for this transformation.
Since the pioneering studies on Michael reaction with proline ca-
talysis by Barbas,8a List,8b and Enders,8c processes promoted by
chiral amines have been extensively investigated. Representative
catalysts in this area include pyrrolidine diamines,9 pyrrolidine
tetrazole,10 pyrrolidine–pyridine,11 pyrrolidine sulfonamide,12
simple peptides,13 chiral ionic liquid,14 amine thiourea de-
rivatives,15 and cinchona alkaloid.16 Among them, the bifunctional
amine thioureas have been identified as powerful catalysts for
Michael addition of nitroolefins due to the efficient activation of
nitro group by hydrogen bonding. In the course of our interest in
aminocatalysis, especially enamine catalysis using chiral amines
bearing hydrogen bonding donors for a diverse range of trans-
formations of carbonyl compounds,15e–f,17 we have recently dis-
1f:
R1= 4-MeC6H4
Scheme 1. Catalysts evaluated in this study.
O
O
Ar
NO2
NO2
1f/PhCO2H (10 mol %)
Ar
H2O, 35 °C
(1)
dr (syn:anti) up to 99:1
ee (syn) up to 98%
On the other hand, new synthetic strategies that facilitate the
rapid and efficient construction of complex molecules with multi-
ple stereogenic centers remain a preeminent but challenging goal
in modern organic chemistry. Asymmetric desymmetrization (ADS)
of prochiral substrates has been considered as one of the most
useful accesses to this purpose.18 Along this line, the ADS of meso-
and prochiral substrates using enzymatic catalytic18b,19 and metal
catalytic methods18c,20 have been well documented. Nevertheless,
the ADS reaction employing small organic molecule catalysis is still
rare. In 2005, Barbas and co-workers reported an ADS of highly
covered
a family of pyrrolidine–thiourea based catalysts (1)
(Scheme 1). Due to its pyrrolidine backbone and strong activation of
* Corresponding author. Tel./fax: þ86 027 6786 2041.
E-mail address: wxiao@mail.ccnu.edu.cn (W.-J. Xiao).
substituted meso-ketones catalyzed by L
-proline21; then Hayashi,22a
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.005

J.-R. Chen et al. / Tetrahedron 65 (2009) 9238–9243
9239
Rovis,22b and co-workers described asymmetric desymmetrization
of cyclohexadienones. Very recently, Gong,23a Cheng,23b and co-
workers developed the first organocatalytic ADS of prochiral cy-
clohexanones by direct aldol and Michael reactions, respectively.
While some of these existing strategies have been successful, the
development of catalytic, enantioselective methods for the
desymmetrization of prochiral ketones with novel and efficient
organocatalysts is still highly desirable. As part of our efforts to
develop readily tunable organocatalysts of broad utility for chem-
ical transformations, we considered the possibility to extend the
hydrogen bonding activation mode to asymmetric desymmetriza-
tion of prochiral ketones. We envisaged that the ‘tunable’ proper-
ties of the hydrogen bondings at chiral pyrrolidine–thiourea
scaffold (Scheme 1) might remove the symmetry (C4 position) of
prochiral ketones by asymmetric Michael reaction. Herein, we
present the development of a new bifunctional organocatalyst for
desymmetrization of prochiral cyclohexanones via organocatalytic
Michael reactions.
of this kind of catalyst were screened in this reaction, the catalyst
(3) derived from 3-hydroxy-2-naphthoic acid appeared to be the
most effective candidate (Table 1, entry 10). Further examination of
the solvent effect revealed that CH2Cl2 was the suitable one (Table
1, entries 11–16).
With the optimal reaction conditions in hand, the substrate
scope of this reaction was next examined. Firstly, a range of nitro-
styrenes were tested in the ADS of 4-methylcyclohexanone. As
summarized in Table 2, the electronic feature of the substituents
has little influence on the reactivity and selectivity; both electron-
donating and withdrawing substituents in the aromatic ring of
nitrostyrenes are well tolerated in this reaction, providing the
products with good to excellent selectivity (Table 2, entries 1–6).
Exploring of ketone scope, we found a variety of substituted cy-
clohexanones were efficiently desymmetrized in this reaction. For
these more hindered ketones, the electronic feature of the sub-
stituent on nitrostyrenes have obviously effect on the reactivity and
selectivity of this reaction. Electron deficient nitrostyrene provided
the products with higher selectivity than neutral or electron suf-
ficient ones (Table 2, entries 8 vs 7 and 9, entries 11 vs 10 and 12). It
is worthwhile that the desymmetrization of hetero-cyclohexa-
nones can also be realized with excellent diastereoselectivities al-
beit with moderate enantioselectivities (Table 2, entries 13–16).
To determine the generality of catalyst 3, we further detect the
catalytic activity of 3 in the direct Michael reaction of cyclohexa-
none with nitrostyrenes. Optimization of the reaction conditions
shows that water was the best medium with PhCO2H as cocatalyst.
The loading of the catalyst can even be reduced to 5 mol % (see
Supplementary data for details).
2. Results and discussion
We first screened the ability of this type of organocatalysts (1a–f)
in the Michael reaction of 4-methylcyclohexanone (4a) with
b
-nitrostyrene (5a). The desired Michael adducts were obtained in
moderate to good yields with good enantioselectivity (Table 1,
entries 1–6). For example, the major isomer 6aa has 88% ee in the
presence of chiral thiourea 1f. Other diastereoisomers were
detected only in trace amounts. Note that the thiourea motif (1a–f)
has effective impact on the enantioselectivity and rate of the re-
action. With this analogy in mind, we synthesized salicylic amides
as a new class of organocatalysts and applied them to this
desymmetrization process. We further examined the influence of
the structure of H-bonding donor on this transformation. We were
delighted to find that salicylic amide 2a efficiently catalyze this
reaction, giving the product with comparable enantio- and dia-
stereoselectivity (Table 1, entry 7 vs 6). Then several other analogs
Table 2
ADS of 4-substituted cyclohexanone via asymmetric Michael addition to
nitrostyrenesa
O
O
Ar
O
Ar
NO2
NO2
3
NO2
/PhCO2H (10 mol%)
+
Ar
+
CH2Cl2 ( 0.5 M), rt
X
R
4a-g
X
R
X
R
5a-f
6aa-ga
6aa'-ga'
Table 1
Optimization of reaction conditions for the ADS of 4-methylcyclohexanonea
Entrya X–R
Ar
Time Product Yieldb drc
eed
(%)
O
Ph
O
O
Ph
(h)
(%)
organocat./PhCO2H
(10 mol %)
NO2
NO2
NO2
1
2
3
4
5
6
CH–CH3(4a)
CH–CH3(4a)
CH–CH3(4a)
CH–CH3(4a)
CH–CH3(4a)
CH–CH3(4a)
Ph(5a)
p-F-Ph(5b)
p-CI-Ph(5c)
p-Br-Ph(5d) 10
p-Me-Ph(5e) 10
p-MeO-Ph
(5f)
12
10
10
6aa
6ab
6ac
6ad
6ae
6af
78
95
77
76
90
63
>99:1
91:9
98:2
90:10 88
90:10 74
99:1
93
90
88
+
Ph
+
Solvent, rt
4a
5a
6aa
6aa'
10
83
Entrya
Cat.
Solvent
CH2Cl2
Time (h)
Yieldb (%)
drc
eed (%)
7
8
9
CH–C2H5(4b) Ph(5a)
CH–C2H5(4b) p-F-Ph(5b)
CH–C2H5(4b) p-MeO-Ph
(5f)
17
10
32
6ba
6bb
6bf
59
87
90
97:3
99:1
98:2
83
90
77
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
2a
2b
2c
3
3
3
3
3
3
3
24
32
32
36
24
32
12
29
29
12
14
17
12
12
20
20
66
48
74
70
82
80
80
74
76
78
64
63
69
79
82
71
88:12
95:5
95:5
92:8
94:6
98:2
95:5
98:2
98:2
>99:1
99:1
96:4
96:4
97:3
93:7
81:19
82
89
85
84
80
88
86
87
87
93
84
88
86
82
86
90
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
10
11
12
CH–Ph(4c)
CH–Ph(4c)
CH–Ph(4c)
Ph(5a)
23
9
23
6ca
6cb
6cf
56
67
90
97:3
94:6
99:1
83
90
80
p-F-Ph(5b)
p-MeO-Ph
(5f)
13
C(OCH2CH2O) Ph(5a)
(4d)
34
6da
67
90:10 78
9
10
11
12
13
14
15e
16f
14
15
16
N-Boc(4e)
S(4f)
O(4g)
Ph(5a)
Ph(5a)
Ph(5a)
40
10
48
6ea
6fa
6ga
88
77
60
99:1
97:3
97:3
60
80
50
THF
n-Hexane
Toluene
CH2Cl2
d
a
All reactions were carried out under the optimal conditions: 5.0 mmol 4,
0.5 mmol 5, 10 mol % 3/PhCO2H, 1 mL CH2Cl2. The absolute configuration of the
major product was determined by the comparison of HPLC retention times with
those in the literature.9
a
Reactions were run on a scale of 5.0 mmol 4a, 0.5 mmol 5a, 10 mol % organocat./
b
Isolated yield.
PhCO2H.
c
Determined by 1H NMR analysis of the crude products.
b
c
d
e
f
Isolated yield.
d
Ratio of 6aa:6aa0, determined by 1H NMR analysis of the crude products.
Determined by chiral HPLC.
Determined by chiral HPLC.
0.5 mL of CH2Cl2 was used.
Neat.
As illustrated in Table 3, catalyst 3 also showed excellent ability
in controlling the enantio- and diastereoselectivity of this reaction.

9240
J.-R. Chen et al. / Tetrahedron 65 (2009) 9238–9243
Table 3
methane and trichloromethane were freshly distilled from calcium
hydride. Hexane and ethyl acetate for flash column chromatography
were distilled before use. Flash column chromatography was per-
formed using 200–300 mesh silica gel. Infrared spectra were
recorded on a Perkin–Elmer PE-983 spectrometer as KBr film with
absorption in cmꢀ1. 1H NMR spectra were recorded on Varian Mer-
cury 400 (400 MHz) spectrophotometers. Chemical shifts are
reported in parts per million from the solvent resonance as the in-
ternal standard (CDCl3: 7.26 ppm). Data are reported as follows:
chemical shift, multiplicity (s¼single, d¼doublet, t¼triplet,
q¼quartet, br¼broad, m¼multiplet), coupling constants (Hz), and
integration. 13C NMR spectra were recorded on Varian Mercury 400
(100 MHz) with complete proton decoupling spectrophotometers
(CDCl3: 77.0 ppm). Chiral HPLC was performed on Agilent 1100 se-
ries with chiral columns (Chiralpak AS, AD, OD, and OJ columns
(Daicel Chemical Ind., Ltd)). Elementary analysis was taken on
a Vario EL III elementary analysis instrument. Mass spectra analysis
was performed on API 200 LC/MS system (Applied Biosystems Co.
Ltd).
Salicylic amide 3 catalyzed asymmetric Michael addition of cyclohexanone with
nitrostyrenes in watera
O
O
Ar
NO2
NO2
3/PhCO2H (5 mol %)
H2O (0.5 mL), rt
Ar
+
4h
5a-j
6ha-hj
Entrya Ar
Time (h) Product Yieldb (%) dr (syn:anti)c eec (%)
1
2
3
4
5
6
7
8
9
10
Ph(5a)
8
10
13
11
5
6
11
5
6ha
6hb
6hc
6hd
6he
6hf
6hg
6hh
6hi
83
80
69
82
93
89
83
74
80
81
99:1
94:6
88:12
98:2
97:3
98:2
94:6
95:5
99:1
90:10
96
92
88
90
94
93
92
86
92
80
p-FPh(5b)
p-ClPh(5c)
p-BrPh(5d)
p-MePh(5e)
o-ClPh(5f)
o-FPh(5g)
m-PhOPh(5h)
2,4-ClPh(5i)
2-Thienyl(5j)
5
6
6hj
a
All reactions were run in the presence of 3/PhCO2H (5 mol %) on 0.25 mmol scale
in 0.5 mL H2O at rt.
b
4.2. General procedures for preparation of thiourea catalysts
2a–c and 3
Isolated yield.
Determined by chiral HPLC.
c
Significant structural variation in the nitrostyrene component can
be realized (Table 3). The reaction displays obvious generality and
functional-group tolerance. Both electron-donating and with-
drawing substrates could be utilized without substantial loss in
selectivity (dr up to 99:1, ee up to 96%) and yield (up to 93%). A
heteroaromatic nitrostyrene also worked well in this reaction with
somewhat lower ee (Table 3, entry 10).
The absolute configuration of the major isomer in the reaction of
4-substituted cyclohexanones with a variety of nitrostyrenes was
determined to be (20R,2S,4S) by comparison of the HPLC data with
the known literature.23b To explain the excellent selectivity of this
reaction, we proposed that the catalytic mode of 3 should be similar
to the thiourea catalyst, reported by the Tang15d and our groups,15e,f
respectively. The pyrrolidine motif efficiently activates the ketone
via enamine intermediate; meanwhile, the NH of the amide and the
adjacent OH presumably provide double hydrogen bond to activate
and orientate the nitrostyrenes (Fig. 1).
3-Hydroxy-2-naphthoic acid (1.26 g, 6.7 mmol) was dissolved in
10 mL THF. The mixture was cooled to 0 ꢁC. Then DCC (1.39 g
6.7 mmol) and HOBt (0.91 g, 6.7 mmol) were added into this so-
lution. And N-Boc-(S)-2-aminomethylpyrrolidine (1.0 g, 5 mmol,
prepared according to the known procedure in five steps from
L
-proline10) was introduced into the solution by dropwise at 0 ꢁC.
After the addition was completed, the mixture was allowed to
warm to room temperature and stirred for an appropriate time
(monitored by TLC, petroleum ether/ethyl acetate¼3:1). When the
reaction was completed, the solvent was removed under reduced
pressure. The residue was directly subjected to the next step
ddissolved in a mixture of TFA/CH2Cl2¼1:4 (20 mL) and stirred for
2 h at room temperature. The mixture was basified with concen-
trated ammonia solution and extracted with CH2Cl2 (3ꢂ30 mL).
After the removal of the solvent under reduced pressure, the resi-
due was purified through flash column chromatography on silica
gel (eluent, ethyl acetate/methanol¼1:1) to yield 3 as a yellow solid
in 70% yield.
O
N
N
N
4.2.1. Catalyst 2a. The title compound was prepared according to
more close-knit
N
S
O
O
H
H
the typical procedure, as described above in 78% yield. White solid.
N
N
N
O
O
H
Ph
O
1H NMR (400 MHz, CDCl3, TMS):
d 7.56–7.54 (m, 1H), 7.34–7.27 (m,
Ph
R
H
R'
X
X
1H), 6.91–6.78 (br s, 2H), 3.59–3.56 (m, 1H), 3.46–3.43 (m, 1H),
3.30–3.25 (m, 1H), 2.98–2.94 (m, 2H), 1.94–1.74 (m, 3H), 1.49–1.44
Figure 1. Improvement on of H-bonding interaction model.
(m, 1H). 13C NMR (100 MHz, CDCl3, TMS):
d 169.3, 154.2, 135.9,
3. Conclusions
134.3, 126.5, 118.2, 109.5, 60.2, 45.2, 40.5, 33.6, 24.0. Anal. Calcd for
C12H16N2O2: C, 65.43; H, 7.32; N, 12.72. Found: C, 65.37; H, 7.43; N,
12.70. MS: m/z, 220.1.
In summary, we have developed a new bifunctional catalyst for
the desymmetrization of prochiral cyclohexanone by direct Mi-
chael reaction. The optimal organocatalyst (3), which is readily
accessible from commercially available material, tolerates a range
of 4-substituted cyclohexanones and nitrostyrenes and provide for
the desired products with three newly generated stereogenic cen-
ters in high yields and with excellent diastereo- and enantiose-
lectivities. The extension of substrate scope and application of this
catalyst in other reactions are ongoing in our laboratory.
4.2.2. Catalyst 2b. The title compound was prepared according to
the typical procedure, as described above in 78% yield. White solid.
1H NMR (400 MHz, CDCl3, TMS):
d 9.65 (br s, 1H), 8.37 (s, 1H), 7.54
(d, J¼7.2 Hz,1H), 6.38–6.34 (m, 2H), 3.83 (s,1H), 3.75 (s, 3H), 3.64 (s,
1H), 3.24 (s, 2H), 2.08–1.75 (m, 5H). 13C NMR (100 MHz, CDCl3,
TMS): d 171.4, 164.6, 162.9, 128.5, 107.0, 106.8, 101.4, 60.6, 55.3, 45.3,
40.5, 27.3, 23.9. Anal. Calcd for C13H18N2O3: C, 62.38; H, 7.25; N,
11.19. Found: C, 62.11; H, 7.23; N, 11.05. MS: m/z, 250.1.
4. Experimental section
4.1. General remarks
4.2.3. Catalyst 2c. The title compound was prepared according to
the typical procedure, as described above in 78% yield. White solid.
1H NMR (400 MHz, CDCl3, TMS):
1H), 7.21 (s, 1H), 3.84–3.68 (m, 2H), 3.63–3.60 (m, 2H), 3.37–3.30
(m, 1H), 3.18–3.13 (m, 2H), 2.85–2.78 (m, 1H), 2.08–1.70 (m, 4H),
d
8.55 (br s, 1H), 7.33 (d, J¼2.0 Hz,
Unless otherwise noted, material were purchased from commer-
cial suppliers and used without further purification. Dichloro-

J.-R. Chen et al. / Tetrahedron 65 (2009) 9238–9243
9241
1.22 (d, J¼6.8 Hz, 6H), 1.20 (d, J¼6.8 Hz, 6H). 13C NMR (100 MHz,
31.9, 21.1. Anal. Calcd for C15H18ClNO3: C, 60.91; H, 6.13; N, 4.74.
Found: C, 60.88; H, 6.09; N, 4.76. MS: m/z, 259.0. HPLC (Chiralpak
CDCl3, TMS):
d
172.2, 157.2, 138.9, 137.3, 129.5, 121.2, 112.5, 60.2,
45.2, 40.5, 33.6, 27.7, 26.6, 24.1, 24.0, 22.4. Anal. Calcd for
C18H28N2O2: C, 71.02; H, 9.27; N, 9.20. Found: C, 70.94; H, 9.14; N,
9.08. MS: m/z, 304.0.
AD-H, i-propanol/hexane¼2:98, flow rate 1.0 mL/min, ¼230 nm):
l
tminor¼35.1 min, tmajor¼40.0 min; ee¼88%. Rf¼0.63 (petroleum
ether/ethyl acetate¼5:1).
4.2.4. Catalyst 3. The title compound was prepared according to
4.3.4. (2S,4S)-2-((R)-1-(4-Bromophenyl)-2-nitroethyl)-4-methyl-
cyclohexanone (6ad). The title compound was prepared according
to the typical procedure, as described above in 76% yield. Colorless
the typical procedure, as described above in 78% yield. White solid.
1H NMR (400 MHz, CDCl3, TMS):
d 8.12 (s, 1H), 7.67–7.60 (m, 2H),
7.44–7.41 (m, 1H), 7.25–7.20 (m, 2H), 4.19 (br s, 3H), 3.64–3.35 (m,
oil. 1H NMR (400 MHz, CDCl3, TMS):
d 7.49–7.05 (m, 4H), 4.98–4.54
3H), 3.06–3.00 (m, 2H), 2.02–1.86 (m, 3H), 1.52–1.47 (m, 1H). 13C
(m, 2H), 3.93–3.71 (m, 1H), 2.79–2.69 (m, 1H), 2.54–2.30 (m, 2H),
2.06–1.86 (m, 2H), 1.68–1.62 (m, 2H), 1.49–1.26 (m, 1H), 1.01–0.97
NMR (100 MHz, CDCl3, TMS):
d 169.4, 158.9, 137.0, 130.7, 128.9,
127.7, 126.1, 120.3, 112.3, 59.5, 45.7, 42.7, 42.6, 28.7, 24.9. Anal. Calcd
for C16H18N2O2: C, 71.09; H, 6.71; N, 10.36. Found: C, 70.74; H, 6.14;
N, 9.88. MS: m/z, 270.3.
(m, 3H). 13C NMR (100 MHz, CDCl3, TMS):
d 210.7, 137.6, 130.5, 121.8,
77.7, 52.8, 43.1, 41.9, 38.4, 35.5, 32.3, 21.5. Anal. Calcd for
C15H18BrNO3: C, 52.96; H, 5.83; N, 4.12. Found: C, 52.90; H, 5.91; N,
4.04. MS: m/z, 339.1. HPLC (Chiralpak AD-H, i-propanol/
4.3. General procedure for the Michael addition (Table 2)
hexane¼5:95, flow rate 1.0 mL/min,
l
¼230 nm): tminor¼33.3 min,
tmajor¼36.7 min; ee¼88%. Rf¼0.75 (petroleum ether/ethyl
acetate¼5:1).
Catalyst (0.05 mmol), PhCO2H (0.05 mmol), and 10 equiv
cyclohexanone were dissolved in 1 mL CH2Cl2. After the mixture
was stirred for 15 min at room temperature, the corresponding
nitroolefin (0.5 mmol) was added and the mixture was stirred for
an appropriate time (monitored by TLC, petroleum ether/ethyl
acetate¼5:1). The reaction mixture was purified by flash column
chromatography on silica gel (petroleum ether/ethyl acetate¼
20:1–5:1) to gain the desired product as oil or solid. Relative and
absolute configurations of the products were determined by com-
parison with the known 1H NMR, 13C NMR, and chiral HPLC
analysis.
4.3.5. (2S,4S)-4-Methyl-2-((R)-2-nitro-1-p-tolylethyl)cyclohexanone
(6ae). The title compound was prepared according to the typical
procedure, as described above in 90% yield. Light yellow oil. 1H NMR
(400 MHz, CDCl3, TMS):
d
7.15–7.04 (m, 4H), 4.67 (dd, J¼4.6,12.6 Hz,
1H), 4.57 (dd, J¼12.4, 12.8 Hz, 1H), 2.77–2.67 (m, 1H), 2.54–2.36 (m,
2H), 2.31 (s, 3H), 2.08–1.91 (m, 2H), 1.63–1.60 (m, 1H), 1.50–1.34 (m,
2H), 0.96 (d, J¼6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3, TMS):
d 213.0,
137.6,134.0,129.8,129.5,127.9,127.7, 79.1, 50.1, 43.7, 38.4, 34.3, 26.4,
21.0, 20.9, 19.4. Anal. Calcd for C16H21NO3: C, 69.79; H, 7.69; N, 5.09.
Found: C, 69.85; H, 7.52; N, 5.01. MS: m/z, 275.1. HPLC (Chiralpak
4.3.1. (2S,4S)-4-Methyl-2-((R)-2-nitro-1-phenylethyl)cyclohexanone
(6aa). The title compound was prepared according to the typical
procedure, as described above in 78% yield. Light yellow oil. 1H NMR
OD-H, i-propanol/hexane¼1:99, flow rate 1.0 mL/min, ¼230 nm):
l
tminor¼25.3 min, tmajor¼26.7 min; ee¼74%. Rf¼0.60 (petroleum
ether/ethyl acetate¼5:1).
(400 MHz, CDCl3, TMS):
d
7.56–7.16 (m, 5H), 4.70 (dd, J¼4.6,12.7 Hz,
1H), 4.61 (dd, J¼10.1, 12.6 Hz, 1H), 3.84–3.77 (m, 1H), 2.76–2.70 (m,
4.3.6. (2S,4S)-2-((R)-1-(4-Methoxyphenyl)-2-nitroethyl)-4-methyl-
cyclohexanone (6af). The title compound was prepared according
to the typical procedure, as described above in 63% yield. Light
1H), 2.52–2.49 (m, 2H), 2.08–1.97 (m, 1H), 1.67–1.39 (m, 4H), 0.97
(d, J¼6.7 Hz, 3H). 13C NMR (100 MHz, CDCl3, TMS):
d 212.9, 137.2,
128.9, 128.6, 128.2, 128.1, 127.9, 79.0, 52.7, 49.9, 43.9, 38.4, 34.3,
26.4, 19.2. Anal. Calcd for C15H19NO3: C, 68.94; H, 7.33; N, 5.36.
Found: C, 68.90; H, 7.15; N, 5.35. MS: m/z, 261.1. HPLC (Chiralpak
yellow oil. 1H NMR (400 MHz, CDCl3, TMS):
d 7.19–7.07 (m, 2H),
6.88–6.83 (m, 2H), 4.83 (dd, J¼6, 9.2 Hz,1H), 4.60 (m,1H), 3.94–3.73
(m, 4H), 2.78–2.64 (m, 1H), 2.51–2.33 (m, 2H), 2.05–1.96 (m, 2H),
1.74–1.08 (m, 3H), 0.97 (d, J¼6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3,
AS-H, i-propanol/hexane¼10:90, flow rate 1.0 mL/min, ¼230 nm):
l
tminor¼18.1 min, tmajor¼36.9 min; ee¼93%. Rf¼0.36 (petroleum
ether/ethyl acetate¼5:1).
TMS): d 213.1, 158.7, 130.1, 129.4, 129.1, 128.9, 114.3, 79.2, 55.1, 43.3,
38.5, 31.9, 26.4, 21.2. Anal. Calcd for C16H21NO4: C, 65.96; H, 7.27; N,
4.81. Found: C, 65.90; H, 7.35; N, 4.73. MS: m/z, 291.0 HPLC (Chir-
alpak AD-HþOD-H, i-propanol/hexane¼5:95, flow rate 1.0 mL/min,
4.3.2. (2S,4S)-2-((R)-1-(4-Fluorophenyl)-2-nitroethyl)-4-methyl-
cyclohexanone (6ab). The title compound was prepared according
to the typical procedure, as described above in 95% yield. Colorless
l
¼230 nm): tminor¼53.3 min, tmajor¼55.5 min; ee¼83%. Rf¼0.40
(petroleum ether/ethyl acetate¼5:1).
oil. 1H NMR (400 MHz, CDCl3, TMS):
d 7.36–7.02 (m, 5H), 4.97–4.67
(m, 2H), 4.34–3.95 (m, 1H), 2.95–2.87 (m, 1H), 2.52–2.35 (m, 2H),
2.07–1.88 (m, 2H), 1.73–1.59 (m, 4H), 1.03–0.97 (m, 3H), 0.88–0.86
4.3.7. (2S,4S)-4-Ethyl-2-((R)-1-(4-fluorophenyl)-2-nitroethyl)cyclo-
hexanone (6bb). The title compound was prepared according to the
typical procedure, as described above in 87% yield. Light yellow solid.
(m, 1H). 13C NMR (100 MHz, CDCl3, TMS):
d 212.5, 162.4, 159.9,
130.5, 129.7, 124.7, 124.3, 115.9, 77.6, 51.5, 47.9, 39.7, 38.3, 34.1, 26.6,
18.9. Anal. Calcd for C15H18FNO3: C, 64.50; H, 6.50; N, 5.01. Found: C,
64.58; H, 6.43; N, 5.07. MS: m/z, 279.0. HPLC (Chiralpak AD-HþOD-
1H NMR (400 MHz, CDCl3, TMS):
d
7.31–7.05 (m, 4H), 4.77 (dd, J¼4.8,
12.8 Hz, 1H), 4.70 (dd, J¼9.9, 12.9 Hz, 1H), 4.06–4.00 (m, 1H), 2.90–
2.84 (m,1H), 2.50–2.43 (m, 2H),1.99–1.93 (m,1H),1.75–1.70 (m, 2H),
1.48–1.29 (m, 4H), 0.80 (t, J¼7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3,
H, i-propanol/hexane¼5:95, flow rate 1.0 mL/min,
l
¼230 nm):
tminor¼29.6 min, tmajor¼33.0 min; ee¼90%. Rf¼0.44 (petroleum
ether/ethyl acetate¼5:1).
TMS): d 212.7, 130.6, 129.8, 129.7, 124.7, 116.1, 115.1, 78.8, 55.8, 48.0,
39.7, 35.6, 33.5, 25.7, 11.7. Anal. Calcd for C16H20FNO3: C, 65.51; H,
6.87; N, 4.78. Found: C, 65.48; H, 6.87; N, 4.71. MS: m/z, 293.0. HPLC
(Chiralpak AD-HþOD-H, i-propanol/hexane¼5:95, flow rate 1.0 mL/
4.3.3. (2S,4S)-2-((R)-1-(4-Chlorophenyl)-2-nitroethyl)-4-methyl-
cyclohexanone (6ac). The title compound was prepared according
to the typical procedure, as described above in 77% yield. Colorless
min,
l
¼230 nm): tminor¼31.2 min, tmajor¼39.2 min; ee¼90%. Rf¼0.84
(petroleum ether/ethyl acetate¼5:1).
oil. 1H NMR (400 MHz, CDCl3, TMS):
d 7.39–7.34 (m, 2H), 7.29–7.20
(m, 2H), 5.02–4.63 (m, 2H), 4.02–3.80 (m, 1H), 2.87–2.75 (m, 1H),
2.54–2.41 (m, 2H), 2.11–1.96 (m, 2H), 1.74–1.33 (m, 2H), 1.17–1.14
(m, 1H), 1.03 (d, J¼6.0 Hz, 3H). 13C NMR (100 MHz, CDCl3, TMS):
4.3.8. (2S,4S)-4-Ethyl-2-((R)-1-(4-methoxyphenyl)-2-nitroethyl)-
cyclohexanone (6bf). The title compound was prepared according
to the typical procedure, as described above in 90% yield. Light
d
210.4, 136.8, 133.2, 129.8, 128.8, 78.5, 52.5, 42.5, 41.4, 37.9, 35.1,
yellow solid. 1H NMR (400 MHz, CDCl3, TMS):
d 7.10–7.08 (m, 2H),

9242
J.-R. Chen et al. / Tetrahedron 65 (2009) 9238–9243
6.88–6.83 (m, 2H), 4.68 (dd, J¼12.0, 12.0 Hz, 1H), 4.60 (dd, J¼16.0,
24.0 Hz, 1H), 3.78 (s, 3H), 2.70–2.58 (m, 1H), 2.50–2.43 (m, 2H),
1.99–1.93 (m, 1H), 1.73–1.61 (m, 2H), 1.48–1.29 (m, 4H), 0.80 (t,
hexane¼10:90, flow rate 1.0 mL/min, ¼230 nm): tminor¼29.6 min,
l
tmajor¼50.4 min; ee¼78%. Rf¼0.33 (petroleum ether/ethyl
acetate¼4:1).
J¼7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3, TMS):
d 213.2, 159.0, 128.9,
128.8, 114.3, 79.2, 55.1, 50.2, 43.3, 38.6, 35.2, 33.3, 32.1, 26.3, 11.8.
Anal. Calcd for C17H23NO4: C, 66.86; H, 7.59; N, 4.59. Found: C,
66.65; H, 7.52; N, 4.62. MS: m/z, 305.2. HPLC (Chiralpak OD-H,
4.3.13. (S)-3-((R)-2-Nitro-1-phenylethyl)dihydro-2H-thiopyran-
4(3H)-one (6fa). The title compound was prepared according to the
typical procedure, as described above in 77% yield. White solid. 1H
i-propanol/hexane¼5:95, flow rate 1.0 mL/min,
l
¼230 nm):
NMR (400 MHz, CDCl3, TMS): d 7.37–7.29 (m, 3H), 7.25–7.19 (m, 2H),
tminor¼29.3 min, tmajor¼35.7 min; ee¼77%. Rf¼0.60 (petroleum
ether/ethyl acetate¼5:1).
4.76–4.60 (m, 2H), 4.01–3.95 (m, 1H), 3.08–2.93 (m, 3H), 2.88–2.75
(m, 3H), 2.63–2.59 (m, 1H), 2.48–2.42 (m, 1H). 13C NMR (100 MHz,
CDCl3, TMS): d 209.4, 136.4, 129.2, 128.2, 128.1, 78.5, 54.9, 44.5, 43.4,
4.3.9. (2S,4S)-2-((R)-2-Nitro-1-phenylethyl)-4-phenylcyclohexanone
(6ca). The title compound was prepared according to the typical
procedure, as described above in 56% yield. White solid. 1H NMR
35.0, 31.5. Anal. Calcd for C13H15NO3S: C, 58.55; H, 5.70; N, 5.28.
Found: C, 58.73; H, 5.81; N, 5.24. HPLC (Chiralpak As-H, i-propanol/
hexane¼10:90, flow rate 1.0 mL/min,
l
¼254 nm): tminor¼
(400 MHz, CDCl3, TMS):
d
7.37–7.31 (m, 2H), 7.30–7.26 (m, 3H),
15.66 min, tmajor¼20.00 min; ee¼80%. Rf¼0.45 (petroleum ether/
ethyl acetate¼4:1).
7.24–7.20 (m, 3H), 7.11–7.10 (m, 2H), 4.64 (dd, J¼12.0, 16.0 Hz, 1H),
4.58 (dd, J¼8.0, 12.0 Hz, 1H), 4.12–3.92 (m, 1H), 3.20–3.14 (m, 1H),
2.75–2.70 (m, 2H), 2.60–2.54 (m, 1H), 2.27–2.13 (m, 2H), 1.96–1.89
4.3.14. (R)-3-((R)-2-Nitro-1-phenylethyl)dihydro-2H-pyran-4(3H)-
one (6ga). The title compound was prepared according to the
typical procedure, as described above in 60% yield. White solid. 1H
(m, 1H), 1.76–1.57 (m, 1H). 13C NMR (100 MHz, CDCl3, TMS):
d 212.3,
143.0, 136.7, 129.2, 128.6, 128.2, 127.9, 126.6, 126.4, 79.0, 51.4, 44.0,
38.9, 36.8, 32.6, 29.6. Anal. Calcd for C20H21NO3: C, 74.28; H, 6.55; N,
4.33. Found: C, 74.32; H, 6.51; N, 4.27. MS: m/z, 323.0. HPLC (Chir-
alpak AS-H, i-propanol/hexane¼10:90, flow rate 1.0 mL/min,
NMR (400 MHz, CDCl3, TMS):
d 7.35–7.17 (m, 5H), 4.93 (dd,
J¼4.0 Hz, 1H), 4.63 (dd, J¼10 Hz, 1H), 4.12–4.11 (m, 1H), 3.83–3.66
(m, 3H), 3.28–3.23 (m, 1H), 2.87 (m, 1H), 2.65–2.52 (m, 2H). 13C
l
¼230 nm): tminor¼29.1 min, tmajor¼46.2 min; ee¼83%. Rf¼0.68
NMR (100 MHz, CDCl3, TMS): d 207.3, 136.2, 129.1, 128.2, 127.8, 78.6,
71.5, 68.9, 53.2, 44.5, 42.9, 41.2. Anal. Calcd for C13H15NO4: C, 62.64;
H, 6.07; N, 5.62. Found: C, 62.73; H, 5.97; N, 5.34. HPLC (Chiralpak
(petroleum ether/ethyl acetate¼5:1).
4.3.10. (2S,4S)-2-((R)-1-(4-Fluorophenyl)-2-nitroethyl)-4-phenyl-
cyclohexanone (6cb). The title compound was prepared according
to the typical procedure, as described above in 67% yield. White
AD-H, i-propanol/hexane¼15:85, flow rate 1.0 mL/min, ¼254 nm):
l
tminor¼14.5 min, tmajor¼28.1 min; ee¼50%. Rf¼0.50 (petroleum
ether/ethyl acetate¼4:1).
solid. 1H NMR (400 MHz, CDCl3, TMS):
d 7.34–7.07 (m, 9H), 4.94–
4.67 (m, 2H), 4.43–4.22 (m, 1H), 3.22–3.17 (m, 1H), 3.11–3.05 (m,
1H), 2.89–2.70 (m, 1H), 2.59–2.53 (m, 1H), 2.25–2.22 (m, 2H), 2.00–
1.93 (m, 1H), 1.93–1.62 (m, 3H). 13C NMR (100 MHz, CDCl3, TMS):
4.3.15. (R)-tert-Butyl 3-((R)-2-nitro-1-phenylethyl)-4-oxopiperidine-
1-carboxylate (6ea). The title compound was prepared according to
the typical procedure, as described above in 88% yield. White solid.
d
212.0, 162.4, 159.9, 143.0, 130.0, 129.9, 129.8, 128.6, 126.5, 126.4,
1H NMR (400 MHz, CDCl3, TMS):
d 7.36–7.19 (m, 5H), 4.94 (dd,
124.9, 116.3, 77.4, 50.1, 43.4, 39.9, 38.9, 36.8, 32.4, 29.6. Anal. Calcd
for C20H20FNO3: C, 70.37; H, 5.91; N, 4.10. Found: C, 70.29; H, 5.88;
N, 4.16. MS: m/z, 341.0. HPLC (Chiralpak AD-H¼OD-H, i-propanol/
J¼4.8, 12.4 Hz, 1H), 4.63 (dd, J¼9.6, 12.0 Hz, 1H), 4.21 (s, 1H), 3.79 (s,
1H), 3.19 (s, 2H), 2.79–2.68 (m, 2H), 2.59–2.46 (m, 2H), 1.23 (s, 9H).
13C NMR (100 MHz, CDCl3, TMS):
d 208.3, 154.0, 136.4, 129.1, 128.2,
hexane¼5:95, flow rate 1.0 mL/min,
l¼230 nm): tminor¼53.0 min,
80.7, 78.8, 51.9, 48.1, 44.2, 41.8, 41.7, 28.2. Anal. Calcd for
C18H24N2O5: C, 62.05; H, 6.94; N, 8.04. Found: C, 61.97; H, 6.96; N,
8.02. HPLC (Chiralpak AD-H, i-propanol/hexane¼10:90, flow rate
tmajor¼67.1 min; ee¼90%. Rf¼0.50 (petroleum ether/ethyl
acetate¼5:1).
1.0 mL/min,
Rf¼0.50 (petroleum ether/ethyl acetate¼5:1).
l
¼254 nm): tminor¼13.4 min, tmajor¼15.2 min; ee¼60%.
4.3.11. (2S,4S)-2-((R)-1-(4-Methoxyphenyl)-2-nitroethyl)-4-phenyl-
cyclohexanone (6cf). The title compound was prepared according
to the typical procedure, as described above in 90% yield. White
4.4. General procedure for the Michael addition in water
(Table 3)
solid. 1H NMR (400 MHz, CDCl3, TMS):
d 7.30–7.25 (m, 2H), 7.22–
7.11 (m, 5H), 6.88–6.86 (m, 2H), 4.60 (dd, J¼12.8, 12.8 Hz, 1H), 4.53
(dd, J¼12.8, 12.8 Hz, 1H), 3.93–3.88 (m, 1H), 3.78 (s, 3H), 3.17–3.14
(m, 1H), 2.78–2.59 (m, 2H), 2.59–2.53 (m, 1H), 2.23–2.15 (m, 2H),
1.97–1.90 (m, 1H), 1.75–1.69 (m, 1H). 13C NMR (100 MHz, CDCl3,
Catalyst 3 (0.025 mmol), PhCO2H (0.025 mmol), and 10 equiv
cyclohexanone were dissolved in 0.5 mL H2O. After the mixture was
stirred for 15 min at 35 ꢁC, the corresponding nitroolefin
(0.25 mmol) was added and the mixture was stirred for an appro-
priate time (monitored by TLC, petroleum ether/ethyl acetate¼4:1).
The reaction mixture was then extracted with CH2Cl2, and the
resulting residue was purified by flash column chromatography on
silica gel (petroleum ether/ethyl acetate¼20:1–5:1) to gain the
desired product as a white solid. Relative and absolute configura-
tions of the products were determined by comparison with the
known 1H NMR, 13C NMR, and chiral HPLC analysis. Compounds
6ha–6hj are known.10
TMS):
d 213.2, 159.9, 143.8, 129.6, 129.3, 129.0, 127.3, 115.3, 79.9,
55.9, 52.3, 44.1, 37.5, 36.9, 33.4. Anal. Calcd for C21H23NO4: C, 71.37;
H, 6.56; N, 3.96. Found: C, 71.20; H, 6.44; N, 3.94. MS: m/z, 353.2.
HPLC (Chiralpak AD-HþOD-H, i-propanol/hexane¼15:85, flow rate
1.0 mL/min,
Rf¼0.47 (petroleum ether/ethyl acetate¼5:1).
l
¼230 nm): tminor¼47.4 min, tmajor¼66.0 min; ee¼80%.
4.3.12. (S)-7-((R)-2-Nitro-1-phenylethyl)-1,4-dioxaspiro[4.5]decan-
8-one (6da). The title compound was prepared according to the
typical procedure, as described above in 67% yield. White solid. 1H
NMR (400 MHz, CDCl3, TMS):
d 7.33–7.15 (m, 5H), 4.96–4.58 (m,
2H), 3.97–3.84 (m, 4H), 3.09–3.02 (m, 1H), 2.74–2.62 (m, 1H), 2.47–
Acknowledgements
2.42 (m, 1H), 2.05–1.93 (m, 2H), 1.69–1.51 (m, 2H). 13C NMR
(100 MHz, CDCl3, TMS):
d
210.3, 137.1, 128.9, 128.4, 128.1, 127.8,
We are grateful to the Program for Academic Leader in Wuhan
Municipality (200851430486), and the National Science Founda-
tion of China (20672040 and 20872043) for support of this
research.
106.9, 78.8, 64.7, 64.4, 48.0, 43.3, 39.2, 38.5, 34.9. Anal. Calcd for
C16H19NO5: C, 62.94; H, 6.27; N, 4.59. Found: C, 62.87; H, 6.33; N,
4.61. MS: m/z, 305.0. HPLC (Chiralpak AS-H, i-propanol/

J.-R. Chen et al. / Tetrahedron 65 (2009) 9238–9243
9243
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L.-S.; Guo, H.; Wang, W. Chem.dEur. J. 2006, 12, 4321.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.09.005.
´
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