Chiral 1,1′-binaphthylazepine derived amino alcohol catalyzed asymmetric Henry reaction

Article abstract of DOI:10.1016/j.tetasy.2011.01.026

The catalytic asymmetric Henry reaction of nitromethane to various aldehydes has been developed using a chiral binaphthylazepine derived amino alcohol and Cu(OAc)₂·H₂O as the catalyst. High yields and good enantioselectivities (up to

Full text of DOI:10.1016/j.tetasy.2011.01.026

Tetrahedron: Asymmetry 22 (2011) 238–245
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chiral 1,10-binaphthylazepine derived amino alcohol catalyzed asymmetric
Henry reaction
⇑
⇑
Zong-Liang Guo, Shi Zhong , Yong-Bo Li, Gui Lu
Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The catalytic asymmetric Henry reaction of nitromethane to various aldehydes has been developed using
a chiral binaphthylazepine derived amino alcohol and Cu(OAc)2ꢀH2O as the catalyst. High yields and good
enantioselectivities (up to 97% ee) were obtained for both aromatic and aliphatic aldehydes. Moreover,
this catalytic system also works well for the diastereoselective Henry reaction to afford the corresponding
adducts in up to 95:5 syn/anti selectivity and 95% enantioselectivity.
Received 12 December 2010
Accepted 26 January 2011
Available online 1 March 2011
This paper is dedicated to celebrate the 60th
birthday of Professor Albert S.C. Chan
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
reactions, especially for diastereoselective reactions with a bulky
nitroalkane.
The Henry (nitroaldol) reaction is an important carbon–carbon
bond forming reaction, which can produce a new stereogenic
center at the b-position of the nitro functionality. Since the result-
ing b-nitro alcohol adducts are valuable synthetic intermediate and
useful building blocks for many biological active compounds, much
effort has been focused on the development of the asymmetric
Henry reactions.
Since the first asymmetric version of the Henry reaction was re-
ported by Shibasaki in 1992,1 various effective catalytic systems
based on metal2–6 and non-metals7–13 have been developed.
Amongst them, the copper-containing system is particularly prom-
ising dueto itsambifunctional character,14 resultingin high catalytic
activity and excellent enantioselectivity especially when in combi-
nation with chiral ligands such as bisoxazolines,15–21 (ꢁ)-sparte-
ine,22 bisimidazolines,23,24 diamines,25–33 sulfonyldiamines,34–36
aminopyridines,37,38 salen39–45 and N,N0-dioxides,46 etc.
Although chiral amino alcohols have frequently been used in
catalytic asymmetric synthesis, little research has been carried
out on the copper-amino alcohol catalyzed stereoselective Henry
reaction47–49 and in most cases, only moderate enantioselectivities
have been obtained, which is quite different from the analogous
zinc-amino alcohol systems.50–53
We also noticed that in Arai’s work, chiral binaphthylazepine
derived diamines 128 and sulfonyldiamine 2 (Fig. 1)34,35 exhibited
high efficiencies in the copper catalyzed Henry reaction. The steric
repulsion between the binaphthyl backbone and the two phenyl
groups were hypothesized to provide a better enantio-locking of
the substrate with catalysts, which could be useful for the design
and generation of other effective ligands for asymmetric Henry
Our recent studies involved utilization of the binaphthyl de-
rived amino alcohol (1Ra,2S,3R)-3 as an efficient catalyst for many
asymmetric transformations such as alkynylation and arylation
reaction,54–56 which led us to reexamine this catalyst in the scope
of the classic Henry reaction. Herein we report the development of
a copper(II)-binaphthylazepine derived amino alcohol complex for
the addition of nitroalkanes to a range of aldehydes. This asymmet-
ric Henry reaction proceeds at room temperature and is operation-
ally simple, scalable and has broad functional group compatibility.
2. Results and discussion
2.1. Optimization of the reaction conditions
An initial exploration was performed in the reaction of nitro-
methane with 4-nitrobenzaldehyde using 15 mol % copper salt
and (1Ra,2S,3R)-3. Several commercial available copper salts were
investigated at room temperature. Copper salt Cu(OAc)2 turned
out to be suitable Lewis acid for the model reaction, giving 90%
yield and 87% ee (Table 1, entry 4). Also CuCl and Cu(OTf)2 facili-
tated the reaction and afforded the nitroaldol adduct in good yields
but with poor enantioselectivities (entries 1 and 3). The replace-
ment of Cu(OAc)2 with air stable Cu(OAc)2ꢀH2O showed compara-
ble ees and yields (entries 5 vs 6). Further optimization of
catalyst loading revealed that lowering the ratio of Cu(OAc)2ꢀH2O
from 10 mol % to 5 mol % did not change the conversion or enanti-
oselectivity significantly (entries 6 vs 7).
Next the effect of solvents was tested in the asymmetric Henry
reaction (Table 2). Solvent Et2O seemed to be the best for the reac-
tion, affording the corresponding product in high enantioselectivity
(entry 2), although a longer reaction time (60 h for 4-nitrobenzalde-
hyde) was needed. A further study revealed that for the more inert
⇑
Corresponding authors. Tel./fax: +86 20 39943048.
E-mail address: lugui@mail.sysu.edu.cn (G. Lu).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.01.026

Z.-L. Guo et al. / Tetrahedron: Asymmetry 22 (2011) 238–245
239
Ph
N
Ph
N
Ph
N
Ph
NHSO2R
Ph
N
Ph
OH
1
2
3
Figure 1. Some 1,10-binaphthylazepine derived amino alcohol.
Table 1
Screening of copper salts in the asymmetric Henry reactiona
Ph
N
Ph
OH
O
OH
Copper salt, 3
NO2
H
MeNO2
+
EtOH, rt
O2N
O2N
3
Entry
Copper salt
Catalyst loading (mol %)
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
CuCl
CuBr2
15
15
15
15
10
10
5
24
96
12
24
24
24
24
92
Trace
95
90
90
rac
—
Cu(OTf)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2ꢀH2O
Cu(OAc)2ꢀH2O
rac
87
88
88
87
89
86
a
b
c
All reactions were performed on a 0.375 mmol scale of 4-nitrobenzaldehyde in 1.0 mL ethanol, and 10 equiv of nitromethane was used.
Isolated yield.
Enantiomeric excess was determined by HPLC analysis. The absolute configurations of the products were determined by comparison with the literature values.
Table 2
Effects of solvents in the asymmetric Henry reactiona
Ph
N
Ph
O
OH
Cu(OAc)2 H2O (5 mol%)
3 (5.5 mol%)
NO2
OH
H
MeNO2
+
solvent, rt
O2N
O2N
3
Entry
Solvent
Time (h)
Yieldb (%)
eec (%)
1
THF
Et2O
Et2O
CH2Cl2
Toluene
MeOH
EtOH
EtOH
n-PrOH
48
60
120
48
48
48
24
120
24
60
73
Trace
55
25
80
88
80
62
80
93
—
88
45
73
87
89
83
2
3d
4
5
6
7
8d
9
a
b
c
All reactions were performed on a 0.375 mmol scale of 4-nitrobenzaldehyde in 1.0 mL solvent, and 10 equiv of nitromethane was used.
Isolated yield.
Enantiomeric excess was determined by HPLC analysis. The absolute configurations of the products were determined by comparison with the literature values.
The reaction was performed with benzaldehyde.
d
benzaldehyde substrate, trace product can be obtained even after
120 h in Et2O (entry 3). In general, protic solvents, such as methanol,
ethanol, or n-propanol, helped to accelerate the reaction rate
without compromising the stereoselectivity (entries 6–9). For
example, when EtOH was used, the reaction could be completed in
24 h and obtained with 88% yield and 87% ee (entry 7).

240
Z.-L. Guo et al. / Tetrahedron: Asymmetry 22 (2011) 238–245
Table 3
Effects of organic bases in the asymmetric Henry reactiona
Ph
N
Ph
O
OH
Cu(OAc)2 H2O (5 mol%)
3 (5.5 mol%)
NO2
OH
H
MeNO2
+
Et2O, rt, additive
O2N
O2N
3
Entry
Additive
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
—
Et3N
Pyridine
DMAP
DBU
60
24
48
48
48
24
73
84
52
64
80
83
93
74
34
29
14
75
DIPEA
a
b
c
All reactions were performed on a 0.375 mmol scale of 4-nitrobenzaldehyde in 1.0 mL Et2O, and 10 equiv of nitromethane was used.
Isolated yield.
Enantiomeric excess was determined by HPLC analysis. The absolute configurations of the products were determined by comparison with literature values.
Table 4
Enantioselective Henry reaction of various aldehydes with nitromethane under optimal conditionsa
Ph Ph
OH
Cu(OAc)2 H2O (5 mol%)
O
3 (5.5 mol%)
OH
MeNO2
N
+
NO2
R
H
EtOH, rt
R
4
3
Entry
R
Product
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
C6H5
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
120
24
36
72
96
60
72
72
72
72
48
72
72
72
72
72
72
80
88
83
8
89
87
92
82
91
90
88
89
83
88
91
92
95
91
94
97
96
p-NO2C6H4
o-NO2C6H4
p-OMeC6H4
o-OMeC6H4
p-ClC6H4
o-ClC6H4
p-BrC6H4
m-BrC6H4
p-FC6H4
p-PhC6H4
1-Naphthyl
i-Pr
i-Bu
n-Bu
52
74
65
76
66
71
44
70
65
62
80
79
70
9
10
11
12
13
14
15
16
17
Cyclohexyl
PhCH2CH2
a
b
c
All reactions were performed on a 0.375 mmol scale of 4-nitrobenzaldehyde in 0.5 mL ethanol, and 10 equiv of nitromethane was used.
Isolated yield.
Enantiomeric excess was determined by HPLC analysis. The absolute configurations of the products were determined by comparison with literature values.
We also attempted to improve the efficacy of these transforma-
were obtained by using the (R)-binaphthyl derived amino alcohol 3
(Table 4). Stereoselectivities were not considerably influenced by
the electronic and steric character of substituents in the aromatic
ring, and the enantiomeric purities were moderate to high. For
example, the simplest aromatic aldehydes such as benzaldehyde
was converted to the Henry adduct in 80% yield with 89% ee (entry
1). Aldehydes with electron-withdrawing substituents such as 2-
NO2 and 2-Cl (entries 3 and 7) led to products with similar enanti-
oselectivities to aldehydes with electron-donating substituents
such as 2-OMe (entry 5). The para-substituted aldehydes offered
comparable enantiomeric excess with ortho-substituted aldehydes
(2-Cl vs 4-Cl, entries 6 vs 7). An exception was the deactivated
tions in Et2O, using 20 mol % of an organic base such as Et3N, pyr-
idine, DMAP, DBU or DIPEA as the additive in order to accelerate
the reaction (Table 3), but this led to a significant decrease in ee
values. Hence we chose EtOH as the optimal solvent and used it
for further screening.
2.2. Scope and limitation of the catalytic system
Next, the scope of the reaction was examined. Various aromatic
and aliphatic aldehydes were smoothly converted to b-nitro alco-
hols at room temperature, and in all cases, the (S)-enriched products

Z.-L. Guo et al. / Tetrahedron: Asymmetry 22 (2011) 238–245
241
Table 5
Diastereoselective Henry reactions of various aldehydes with other nitroalkanesa
Ph
N
Ph
OH
Cu(OAc)2 H2O ( 5 mol%) OH
OH
O
3 ( 5.5 mol%)
R2
R2
NO2
anti-5
R2CH2NO2
R1
R1
+
+
R1
H
EtOH, rt
NO2
syn-5
3
Entry
Aldehyde
Isobutyraldehyde
2-Methylbutyraldehyde
Cyclohexanecarboxaldehyde
3-Phenylpropionaldehyde
Isobutyraldehyde
R2CH2NO2
Product
Time (h)
Yieldb (%)
dr (syn/anti)c
ee of synd (%)
1
2
3
4
5
6
EtNO2
EtNO2
EtNO2
EtNO2
PrNO2
PrNO2
5a
5b
5c
5d
5e
5f
72
72
72
72
72
72
77
75
78
73
67
58
95:5
91:9
94:6
80:20
61:39
80:20
95
93
93
91
94
92
3-Phenylpropionaldehyde
a
b
c
All reactions were performed on a 0.375 mmol scale of aldehyde in 0.5 mL ethanol, and 10 equiv of nitroalkane was used.
Isolated yield.
Diastereoselectivity was determined by 1H NMR spectroscopy.
d
Enantiomeric excess was determined by HPLC analysis. The absolute configurations of the products were determined by comparison with literature values.
O
N
O
N
O-
N+
O-
N+
O
O
OH
R1
Cu
Cu
R1
R1
R2
R2
O
O
>
R2
H
H
NO2
H
H
syn-favored
Figure 2. Possible transition structure for the syn-selective Henry reaction.
N1
dihedral angle
57.33°
dihedral angle
N
61.59°
1
Cu
3 Cu
N2
O1
AcO
AcO
AcO2
AcO2
Cu(OAc)2-1
Cu(OAc)2-3
o
o
Bond length (A): Cu-N1: 2.160
Cu-N2: 2.085
Bond length (A): Cu-N : 2.117
Cu-O1: 1.996
Cu-O1: 1.963
Cu-O2: 2.000
Cu-O2: 1.985
Cu-O3: 1.961
the degree of angle: N1-Cu-N2: 84.41°
the degree of angle: N-Cu-O1: 82.43°
Figure 3. Computational geometry of Cu(OAc)2-1 and Cu(OAc)2-3 complexes (Cu: pink; N: blue; O: red; C: grey; H was omitted for clarity).

242
Z.-L. Guo et al. / Tetrahedron: Asymmetry 22 (2011) 238–245
para-anisaldehyde, affording the dehydrated product in large quan-
tity, which could be the result of the increased nucleophilicity of the
substrate (entry 4).
Typically aliphatic aldehydes provided the corresponding ad-
ducts with higher enantioselectivities than aromatic aldehydes
(entries 13–17), in particular a-branched aliphatic aldehydes such
as cyclohexanecarboxaldehyde gave the product with excellent
enantioselectivities of up to 97% (entry 16).
The optimized catalyst system was also applied to the diaste-
reoselective Henry reaction, the latter can form two contiguous
stereogenic centers simultaneously. Since aliphatic aldehydes
showed better enantioselectivities than aromatic aldehydes, we
studied the addition of nitroethane to various aliphatic aldehydes;
the corresponding results are summarized in Table 5. Although the
reaction of nitroethane was slow compared with nitromethane, it
provided the adduct with good syn-selectivity (entries 1–4). Dia-
3. Conclusion
In conclusion, we have demonstrated the application of copper-
binaphthylazepine derived amino alcohol complexes to asymmet-
ric nitroaldol reactions. High yields and good enantioselectivities
were obtained for both aromatic and aliphatic aldehydes. More-
over, this catalytic system also works well for the diastereoselec-
tive Henry reaction to afford the corresponding adducts in up to
95:5 syn/anti selectivity and 95% enantioselectivity. Further de-
tailed mechanistic studies are currently in progress.
4. Experimental
All reactions were carried out in flame-dried glassware under a
nitrogen atmosphere. All solvents were freshly distilled from stan-
dard drying agents. Unless otherwise stated, commercial reagents
purchased from Alfa Aesar, Acros and Aldrich chemical companies
were used without further purification. Purification of reaction
products was carried out by flash chromatography using Qing
Dao Sea Chemical Reagent silica gel (200–300 mesh). 1H NMR
stereoselectivities were significantly improved when the
a-
branched aliphatic aldehydes were used (entries 1 and 3). For
example, the reaction of isobutyraldehyde with nitroethane gave
the product in 77% yield with 95:5 syn/anti selectivity, and the
enantiomeric excess of the syn-adduct was as high as 95% (entry
1). However, in the case of nitropropane, the diastereoselectivity
decreased greatly to 61:39 while the enantiomeric excess of the
major syn isomer remained at 94% for the bulky aliphatic aldehyde
(entries 1 and 5).
These results showed that for the copper catalyzed asymmetric
Henry reaction, binaphthylazepine derived amino alcohol
(1Ra,2S,3R)-3 was superior to sulfonyldiamine 234 in both enanti-
oselectivity and diastereoselectivity, while diamines 128 exhibited
comparable ee but lower dr than 3.
spectra were recorded on
a Bruker Avance III spectrometer
(400 MHz). HPLC analyses were conducted on an Agilent 1200
instrument using Chiralcel OD–H, OJ–H or AD–H columns
(0.46 cm diameter ꢂ 25 cm length). Analytical TLC was performed
using EM separations percolated silica gel 0.2 mm layer UV 254
fluorescent sheets.
4.1. General procedure for the catalytic Henry reaction of
nitroalkanes with aldehydes
At first, (R)-N-[(1S,2R)-1,2-diphenyl-2-hydroxyethyl]-3,5-dihy-
dro-4H-dinaphtho[2,1-c:10,20-e]-azepine 1 (10.1 mg, 0.021 mmol)
and Cu(OAc)2ꢀH2O (3.75 mg, 0.019 mmol) were mixed in 1.0 mL
CH2Cl2 and stirred overnight. Then the solvent was removed under
reduced pressure, after which 0.5 mL EtOH, aldehyde (0.375 mmol)
and nitromethane (0.2 mL, 3.75 mmol) were added to the residue.
After the mixture was stirred at room temperature for 24–72 h, TLC
indicated the completion of the reaction. The volatile components
were removed under reduced pressure and the residue was puri-
fied by a silica gel column chromatography to afford the nitroaldol
adduct. Diastereoselectivity was determined from the 1H NMR
spectrum and the enantiomeric excess was determined by HPLC
analysis.
2.3. Mechanism analysis
This syn-selectivity of the reaction can be explained by a possi-
ble transition state (see Fig. 2).57 The orientation of the substituent
(R1) of the aldehyde could be regulated by the substituent (R2) of
the nitronate and the steric hindrance of the chiral ligand to induce
the direct attack of the aldehyde onto Si-face, establishing the (S)-
configuration at C1 position, whereas in the case of nitroethane,
syn-product was favored. It was expected that the inclusion of
bulky ligands such as binaphthylazepine in the coordination
sphere of copper could result in higher stereocontrol, which was
also proved by our experimental data and the results from Arai
et al.28,34
4.1.1. (S)-2-Nitro-1-phenylethanol 4a14
To rationalize further the stereochemical outcome of the reac-
tion, computational calculations of the geometry of the complexes
Cu(OAc)2-1 and 3 and energetic parameters were also performed
with the BHandHLYP/Gen method using the Gaussian 03 program.
The optimal geometries are presented in Figure 3. It can be seen
that two phenyl rings of the ethylenediamine moiety and the iso-
indoline ring of 1, are all perpendicular to the nearly planar struc-
ture of the tetra-coordinated copper complex. According to the
model proposed by Evans,14 the most reactive transition structure
was the nitromethane perpendicular to the ligand plane and the
aldehyde in the ligand plane. Both Cu(OAc)2-1 and 3 afforded ad-
ducts with an (S)-configuration, indicating that the nitronate at-
tacks the Si-face of the aldehyde. Better enantioselectivity was
achieved by Cu(OAc)2-128 since the perpendicular bulky isoindo-
line ring of 1 limits the orientation of aldehydes more efficiently.
The higher diastereoselectivity of Cu(OAc)2-3 for a nitroalkane
with a large steric hindrance can be explained by Cu(OAc)2-3 pos-
sessing a large dihedral angle between the two naphthyl groups
(61.59°), which together with the more crowded (2S,3R)-dipheny-
lethylenediamine moiety, helped to influence both the axial nitro-
nate and the equatorial aldehyde.
Compound 4a was purified by silica gel column chromatogra-
phy (CH2Cl2/petroleum ether = 3:1) to afford a colorless oil, 80%
yield, 89% ee. 1H NMR (400 MHz, CDCl3): d = 7.38–7.30 (m, 5H),
5.38–5.36 (m, 1H), 4.56–4.51 (m, 1H), 4.44 (dd, 1H, J = 3.2,
13.1 Hz), 3.43 (s, 1H). Enantiomeric excess was determined by
HPLC with a Chiralcel OD–H column (hexane/isopropanol = 90:10,
0.8 mL/min, 215 nm), tmajor = 17.4 min, tminor = 14.5 min.
4.1.2. (S)-2-Nitro-1-(4-nitrophenyl)ethanol 4b14
Compound 4b was purified by silica gel column chromatogra-
phy (CH2Cl2/petroleum ether = 4:1) to afford an off-white solid,
88% yield, 87% ee. 1H NMR (400 MHz, CDCl3): d = 8.27 (d, 1H,
J = 8.2 Hz), 7.64 (d, 1H, J = 8.3 Hz), 5.63–5.61 (m, 1H), 4.65–4.56
(m, 2H), 3.26 (s, 1H). Enantiomeric excess was determined by HPLC
with
a Chiralcel OD–H column (hexane/isopropanol = 85:15,
0.8 mL/min, 254 nm), tmajor = 22.6 min, tminor = 18.8 min.
4.1.3. (S)-2-Nitro-1-(2-nitrophenyl) ethanol 4c14
Compound 4c was purified by silica gel column chromatogra-
phy (CH2Cl2/petroleum ether = 4:1) to afford a brown solid, 83%

Z.-L. Guo et al. / Tetrahedron: Asymmetry 22 (2011) 238–245
243
yield, 92% ee. 1H NMR (400 MHz, CDCl3): d = 8.06–8.03 (m, 1H),
7.95–7.93 (m, 1H), 7.77–7.73 (m, 1H), 7.57–7.52 (m, 1H), 6.02 (d,
1H, J = 7.1 Hz), 4.86–4.82 (m, 1H), 4.58–4.53 (m, 1H), 3.60 (s, 1H).
Enantiomeric excess was determined by HPLC with a Chiralcel
OD–H column (hexane/isopropanol = 90:10, 0.8 mL/min, 215 nm),
tmajor = 17.5 min, tminor = 16.3 min.
4.1.10. (S)-1-(4-Fluorophenyl)-2-nitroethanol 4j14
Compound 4j was purified by silica gel column chromatography
(CH2Cl2/petroleum ether = 1:1) to afford a colorless oil, 71% yield,
88% ee. 1H NMR (400 MHz, CDCl3): d = 7.40–7.36 (m, 2H), 7.11–
7.07 (m, 2H), 5.60–5.43 (m, 1H), 4.61–4.56 (m, 1H), 4.49 (dd, 1H,
J = 3.2, 13.3 Hz), 3.06 (s, 1H). Enantiomeric excess was determined
by HPLC with
nol = 90:10,
a
Chiralcel OD–H column (hexane/isopropa-
4.1.4. (S)-1-(4-Methoxyphenyl)-2-nitroethanol 4d14
0.8 mL/min, 215 nm), tmajor = 14.7 min,
Compound 4d was purified by silica gel column chromatogra-
phy (EtOAc/hexane = 1:9) to afford a colorless oil, 8% yield, 82%
ee. 1H NMR (400 MHz, CDCl3): d = 7.33–7.30 (m, 2H), 6.94–6.90
(m, 2H), 5.40 (dd, 1H, J = 3.0, 9.6 Hz), 4.60 (dd, 1H, J = 9.6,
13.6 Hz), 4.47 (dd, 1H, J = 3.0, 13.6 Hz), 3.81 (s, 3H), 2.79 (br s,
1H). Enantiomeric excess was determined by HPLC with a Chiralcel
OD–H column (hexane/isopropanol = 85:15, 0.8 mL/min, 215 nm),
tmajor = 27.8 min, tminor = 22.1 min.
tminor = 12.7 min.
4.1.11. (S)-1-(Biphenyl-4-yl)-2-nitroethanol 4k14
Compound 4k was purified by silica gel column chromatogra-
phy (CH2Cl2/petroleum ether = 1:1) to afford a yellow solid, 44%
yield, 91% ee. 1H NMR (400 MHz, CDCl3): d = 7.65–7.62 (m, 2H),
7.60–7.56 (m, 2H), 7.43–7.49 (m, 4H), 7.39–7.35 (m, 1H), 5.54–
5.51 (m, 1H), 4.69–4.63 (m, 1H), 4.49 (dd, 1H, J = 3.1, 13.4 Hz).
Enantiomeric excess was determined by HPLC with a Chiralcel
OD–H column (hexane/isopropanol = 90:10, 0.8 mL/min, 215 nm),
tmajor = 27.7 min, tminor = 23.6 min.
4.1.5. (S)-1-(2-Methoxyphenyl)-2-nitroethanol 4e14
Compound 4e was purified by silica gel column chromatogra-
phy (CH2Cl2/petroleum ether = 1:1) to afford a colorless oil, 52%
yield, 91% ee. 1H NMR (400 MHz, CDCl3): d = 7.45–7.42 (m, 1H),
7.36–7.30 (m, 1H), 7.02–6.98 (m, 1H), 6.92–6.90 (d, 1H,
J = 8.4 Hz), 5.61 (m, 1H), 4.63 (dd, 1H, J = 3.2, 13.0 Hz), 4.56 (dd,
1H, J = 9.2, 13.0 Hz), 3.87 (s, 3H), 3.26 (d, 1H, J = 6.2 Hz). Enantio-
meric excess was determined by HPLC with a Chiralcel OD–H col-
4.1.12. (S)-1-(Naphthalen-1-yl)-2-nitroethanol 4l14
Compound 4l was purified by silica gel column chromatography
(CH2Cl2/petroleum ether = 3:1) to afford a yellow solid, 70% yield,
92% ee. 1H NMR (400 MHz, CDCl3): d = 8.00 (d, 1H, J = 8.4 Hz),
7.88 (d, 1H, J = 8.1 Hz), 7.83 (d, 1H, J = 8.2 Hz), 7.72 (d, 1H,
J = 7.2 Hz), 7.59–7.46 (m, 3H), 6.22–6.20 (m, 1H), 4.66–4.58 (m,
2H), 3.18–3.15 (m, 1H). Enantiomeric excess was determined by
HPLC with a Chiralcel OD–H column (hexane/isopropanol = 85:15,
0.8 mL/min, 215 nm), tmajor = 17.9 min, tminor = 12.6 min.
umn
(hexane/isopropanol = 90:10,
0.8 mL/min,
215 nm),
tmajor = 14.5 min, tminor = 12.4 min.
4.1.6. (S)-1-(4-Chlorophenyl)-2-nitroethanol 4f14
Compound 4f was purified by silica gel column chromatography
(CH2Cl2/petroleum ether = 1:1) to afford a colorless oil, 74% yield,
90% ee. 1H NMR (400 MHz, CDCl3): d = 7.39–7.33 (m, 4H), 5.46–
5.42 (m, 1H), 4.57 (dd, 1H, J = 9.4, 13.4 Hz), 4.48 (dd, 1H, J = 3.2,
13.4 Hz), 3.10 (s, 1H). Enantiomeric excess was determined by
HPLC with a Chiralcel OD–H column (hexane/isopropanol = 90:10,
0.8 mL/min, 215 nm), tmajor = 17.3 min, tminor = 14.4 min.
4.1.13. (S)-3-Methyl-1-nitrobutan-2-ol 4m14
Compound 4m was purified by silica gel column chromatogra-
phy (CH2Cl2/petroleum ether = 1:3) to afford a colorless oil, 65%
yield, 95% ee. 1H NMR (400 MHz, CDCl3): d = 4.51–4.38 (m, 2H),
4.12–4.05 (m, 1H), 3.18 (m, 1H), 1.83–1.74 (m, 1H), 1.00–0.96
(m, 6H). Enantiomeric excess was determined by HPLC with a Chi-
ralcel OD–H column (hexane/isopropanol = 98:2, 0.8 mL/min,
215 nm), tmajor = 29.9 min, tminor = 27.7 min.
4.1.7. (S)-1-(2-Chlorophenyl)-2-nitroethanol 4g14
Compound 4g was purified by silica gel column chromatography
(CH2Cl2/petroleum ether = 1:1) to afford a colorless oil, 65% yield,
88% ee. 1H NMR (400 MHz, CDCl3): d = 7.67–7.64 (m, 1H), 7.39–
7.30 (m, 3H), 5.76 (dd, 1H, J = 2.2, 9.6 Hz), 4.59 (dd, 1H, J = 2.4,
13.5 Hz), 4.37 (dd, 1H, J = 9.6, 13.5 Hz), 3.01 (s, 1H). Enantiomeric ex-
cesswasdeterminedbyHPLCwitha ChiralcelOJ–H column(hexane/
4.1.14. (S)-4-Methyl-1-nitropentan-2-ol 4n14
Compound 4n was purified by silica gel column chromatogra-
phy (CH2Cl2/petroleum ether = 1:3) to afford a colorless oil, 62%
yield, 91% ee. 1H NMR (400 MHz, CDCl3): d = 4.43–4.33 (m, 3H),
3.09 (s, 1H), 1.89–1.77 (m, 1H), 1.54–1.43 (m, 1H), 1.27–1.20 (m,
1H), 0.96 (s, 6H). Enantiomeric excess was determined by HPLC
isopropanol = 97:3, 0.8 mL/min, 215 nm), tmajor = 44.6 min, tminor
=
40.2 min.
with
a
Chiralcel OJ–H column (hexane/isopropanol = 98:2,
0.6 mL/min, 215 nm), tmajor = 40.2 min, tminor = 35.9 min.
4.1.8. (S)-1-(4-Bromophenyl)-2-nitroethanol 4h14
4.1.15. (S)-1-Nitrohexan-2-ol 4o14
Compound 4h was purified by silica gel column chromatography
(CH2Cl2/petroleum ether = 1:1) to afford a colorless oil, 76% yield,
89% ee. 1H NMR (400 MHz, CDCl3): d = 7.52–7.50 (m, 2H), 7.27–
7.25 (m, 2H), 4.56–4.52 (m, 1H), 4.39 (dd, 1H, J = 3.3, 13.2 Hz), 3.49
(s, 1H), 2.13 (s, 1H). Enantiomeric excess was determined by HPLC
Compound 4o was purified by silica gel column chromatogra-
phy (CH2Cl2/petroleum ether = 1:3) to afford a colorless oil, 80%
yield, 94% ee. 1H NMR (400 MHz, CDCl3): d = 4.44 (dd, 1H, J = 3.1,
12.7 Hz), 4.40–4.35 (m, 1H), 4.34–4.28 (m, 1H), 3.02 (br s, 1H),
1.57–1.47 (m, 3H), 1.34–1.25 (m, 3H), 0.92 (t, 3H, J = 7.2 Hz). Enan-
tiomeric excess was determined by HPLC with a Chiralcel AD–H
with
a Chiralcel OD–H column (hexane/isopropanol = 90:10,
1.0 mL/min, 215 nm), tmajor = 17.8 min, tminor = 14.1 min.
column (hexane/isopropanol = 98:2, 0.8 mL/min, 215 nm), tmajor
37.5 min, tminor = 29.4 min.
=
4.1.9. (S)-1-(3-Bromophenyl)-2-nitroethanol 4i14
Compound 4i was purified by silica gel column chromatography
(CH2Cl2/petroleum ether = 1:1) to afford a colorless oil, 66% yield,
83% ee. 1H NMR (400 MHz, CDCl3): d 7.57 (s, 1H), 7.49–7.47 (d,
1H, J = 8.0 Hz), 7.33–7.25 (m, 2H), 5.43–5.41 (d, 1H, J = 8.4 Hz),
4.59–4.47 (m, 2H), 3.34 (s, 1H). Enantiomeric excess was deter-
4.1.16. (S)-1-Cyclohexyl-2-nitroethanol 4p14
Compound 4p was purified by silica gel column chromatogra-
phy (CH2Cl2/petroleum ether = 1:3) to afford a colorless oil, 79%
yield, 97% ee. 1H NMR (400 MHz, CDCl3): d = 4.51–4.35 (m, 2H),
4.10–4.01 (m, 1H), 3.27 (br s, 1H), 1.84–1.72 (m, 3H), 1.71–1.60
(m, 2H), 1.50–1.37 (m, 1H), 1.28–1.02 (m, 5H). Enantiomeric excess
was determined by HPLC with a Chiralcel AD–H column (hexane/
mined by HPLC with
a Chiralcel OD–H column (hexane/i-
PrOH = 90:10, 0.8 mL/min, 215 nm), tmajor = 17.6 min, tminor
13.4 min.
=

244
Z.-L. Guo et al. / Tetrahedron: Asymmetry 22 (2011) 238–245
isopropanol = 97:3,
0.8 mL/min,
215 nm),
tmajor = 23.9 min,
4.1.23. (3S,4S)-4-Nitro-1-phenylhexan-3-ol 5f21
tminor = 22.9 min.
Compound 5f was purified by silica gel column chromatography
(EtOAc/hexanes = 15:85) to afford a colorless oil, 58% yield, 80:20
syn/anti, 92% ee (syn). 1H NMR (400 MHz, CDCl3): d = 7.32–7.24
(m, 2H), 7.22–7.15 (m, 3H), 4.40–4.32 (m, 1H), 4.00–3.85 (m,
1H), 2.90–2.82 (m, 1H), 2.74–2.64 (m, 1H), 2.54–2.48 (m, 1H),
2.06–1.70 (m, 4H), 0.96–0.90 (m, 3H). Enantiomeric excess was
determined by HPLC with a Chiralcel OD–H column (hexane/iso-
4.1.17. (S)-1-Nitro-4-phenylbutan-2-ol 4q14
Compound 4q was purified by silica gel column chromatogra-
phy (CH2Cl2/petroleum ether = 1:3) to afford a white solid, 70%
yield, 96% ee. 1H NMR (400 MHz, CDCl3): d = 7.31–7.28 (m, 2H),
7.24–7.18 (m, 3H), 4.38–4.33 (m, 2H), 4.29 (s, 1H), 2.88–2.80 (m,
2H), 2.76–2.69 (m, 1H), 1.89–1.73 (m, 2H). Enantiomeric excess
was determined by HPLC with a Chiralcel OD–H column (hexane/
isopropanol = 90:10, 0.8 mL/min, 215 nm), tmajor = 24.0 min,
tminor = 25.6 min.
propanol = 95:5, 1.0 mL/min, 208 nm), for syn-product, tmajor
18.1 min, tminor = 25.2 min.
=
Acknowledgements
We thank the National Natural Science Foundation of China
(No. 20772161), Scientific Research Foundation for the Returned
Overseas Chinese Scholars and the Program for New Century Excel-
lent Talents in University (both from the State Education Ministry
of China) for financial support of this study.
4.1.18. (3S,4S)-2-Methyl-4-nitropentan-3-ol 5a34
Compound 5a was purified by silica gel column chromatogra-
phy (CH2Cl2/petroleum ether = 1:1) to afford a colorless oil, 77%
yield, 95:5 syn/anti, 95% ee (syn). 1H NMR (400 MHz, CDCl3):
d = 4.62–4.54 (m, 1H), 3.83–3.60 (m, 1H), 2.20 (br s, 1H), 1.82–
1.63 (m, 1H), 1.55–1.52 (m, 3H), 1.00–0.95 (m, 3H), 0.87–0.83
(m, 3H). Enantiomeric excess was determined by HPLC with a Chi-
ralcel OD–H column (hexane/isopropanol = 99:1, 0.8 mL/min,
220 nm), for syn-product, tmajor = 19.2 min, tminor = 16.6 min.
References
1. Sasai, H.; Suzuki, T.; Arai, S.; Arai, T.; Shibasaki, M. J. Am. Chem. Soc. 1992, 114,
4418.
2. Shibasaki, M.; Gröger, H. In Comprehensive Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. III, p 1075.
3. Shibasaki, M.; Gröger, H.; Kanai, M. In Comprehensive Asymmetric Catalysis,
Supplement 1; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer:
Heidelberg, 2004; p 131.
4.1.19. (2S,3S)-5-Methyl-2-nitrohexan-3-ol 5b34
Compound 5b was purified by silica gel column chromatogra-
phy (CH2Cl2/petroleum ether = 1:1) to afford a colorless oil, 75%
yield, 91:9 syn/anti, 93% ee (syn). 1H NMR (400 MHz, CDCl3):
d = 4.47–4.33 (m, 1H), 3.94–3.85 (m, 1H), 2.06 (br s, 1H), 1.94–
1.83 (m, 1H), 1.56–1.53 (m, 3H), 1.44–1.37 (m, 1H), 1.26–1.22
(m, 1H), 0.97–0.93 (m, 6H). Enantiomeric excess was determined
4. Boruwa, J.; Gogoi, N.; Saikia, P. P.; Barua, N. C. Tetrahedron: Asymmetry 2006, 17,
3315.
5. Palomo, C.; Oiarbide, M.; Laso, A. Eur. J. Org. Chem. 2007, 2561.
6. Palomo, C.; Oiarbide, M.; Mielgo, A. Angew. Chem., Int. Ed. 2004, 43, 5442.
7. Ooi, T.; Doda, K.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 2054.
8. Allingham, M. T.; Howard-Jones, A.; Murphy, P. J.; Thomas, D. A.; Caulkett, P. W.
R. Tetrahedron Lett. 2003, 44, 8677.
by HPLC with
a Chiralcel AD–H column (hexane/isopropa-
9. Marcelli, T.; van der Haas, R. N. S.; van Maarseveen, J. H.; Hiemstra, H. Angew.
Chem., Int. Ed. 2006, 45, 929.
nol = 97:3, 0.8 mL/min, 220 nm), for syn-product, tmajor = 16.4 min,
tminor = 15.5 min.
10. Sohtome, Y.; Hashimoto, Y.; Nagasawa, K. Eur. J. Org. Chem. 2006, 13, 2894.
11. Uraguchi, D.; Sakaki, S.; Ooi, T. J. Am. Chem. Soc. 2007, 129, 12392.
12. Ube, H.; Terada, M. Bioorg. Med. Chem. Lett. 2009, 19, 3895.
13. Jammi, S.; Saha, P.; Sanyashi, S.; Sakthivel, S.; Punniyamurthy, T. Tetrahedron
2008, 64, 11724.
14. Evans, D. A.; Seidel, D.; Rueping, M.; Lam, H. W.; Shaw, J. T.; Downey, C. W. J.
Am. Chem. Soc. 2003, 125, 12692.
15. Christensen, C.; Juhl, K.; Jorgensen, K. A. Chem. Commun. 2001, 2222.
16. Christensen, C.; Juhl, K.; Hazell, R. G.; Jorgensen, K. A. J. Org. Chem. 2002, 67,
4875.
17. Risgaard, T.; Gothelf, K. V.; Jorgensen, K. A. Org. Biomol. Chem. 2003, 1, 153.
18. Lu, S. F.; Du, D. M.; Zhang, S. W.; Xu, J. Tetrahedron: Asymmetry 2004, 15, 3433.
19. Du, D. M.; Lu, S. F.; Fang, T.; Xu, J. J. Org. Chem. 2005, 70, 3712.
20. Ginotra, S. K.; Singh, V. K. Org. Biomol. Chem. 2007, 5, 3932.
21. Toussaint, A.; Pfaltz, A. Eur. J. Org. Chem. 2008, 4591.
22. Maheswaran, H.; Prasanth, K. L.; Krishna, G. G.; Ravikumar, K.; Sridhar, B.;
Kantam, M. L. Chem. Commun. 2006, 4066.
4.1.20. (1S,2S)-1-Cyclohexyl-2-nitropropan-1-ol 5c34
Compound 5c was purified by silica gel column chromatogra-
phy (CH2Cl2/petroleum ether = 1:1) to afford a colorless oil, 78%
yield, 94:6 syn/anti, 93% ee (syn). 1H NMR (400 MHz, CDCl3):
d = 4.68–4.56 (m, 1H), 3.87–3.56 (m, 1H), 1.82–1.75 (m, 2H),
1.70–1.63 (m, 2H), 1.56–1.52 (m, 3H), 1.39–0.90 (m, 7H). Enantio-
meric excess was determined by HPLC with a Chiralcel AD–H
column (hexane/isopropanol = 97:3, 1.0 mL/min, 220 nm), for
syn-product, tmajor = 14.0 min, tminor = 21.2 min.
4.1.21. (3S,4S)-4-Nitro-1-phenylpentan-3-ol 5d34
23. Ma, K. Y.; You, J. S. Chem. Eur. J. 2007, 13, 1863.
Compound 5d was purified by silica gel column chromatogra-
phy (CH2Cl2/petroleum ether = 1:1) to afford a colorless oil, 73%
yield, 80:20 syn/anti, 91% ee (syn). 1H NMR (400 MHz, CDCl3):
d = 7.22–7.16 (m, 2H), 7.12–7.05 (m, 3H), 4.56–4.44 (m, 1H),
4.00–3.85 (m, 1H), 2.89–2.82 (m, 1H), 2.74–2.64 (m, 1H), 2.21 (br
s, 1H), 1.86–1.67 (m, 2H), 1.51–1.47 (m, 3H). Enantiomeric excess
was determined by HPLC with a Chiralcel AD–H column (hexane/
24. Bures, F.; Kulhanek, J.; Ruzicka, A. Tetrahedron Lett. 2009, 50, 3042.
25. Arai, T.; Watanabe, M.; Fujiwara, A.; Yokoyama, N.; Yanagisawa, A. Angew.
Chem., Int. Ed. 2006, 45, 5978.
26. Bandini, M.; Piccinelli, F.; Tommasi, S.; Umani-Ronchi, A.; Ventrici, C. Chem.
Commun. 2007, 616.
27. Bandini, M.; Benaglia, M.; Sinisi, R.; Tommasi, S.; Umani-Ronchi, A. Org. Lett.
2007, 9, 2151.
28. Arai, T.; Watanabe, M.; Yanagisawa, A. Org. Lett. 2007, 9, 3595.
29. Kowalczyk, R.; Sidorowicz, L.; Skarzewski, J. Tetrahedron: Asymmetry 2008, 19,
2310.
isopropanol = 96:4, 1.0 mL/min, 220 nm), for syn-product, tmajor
18.7 min, tminor = 17.3 min.
=
30. Selvakumar, S.; Sivasankaran, D.; Singh, V. K. Org. Biomol. Chem. 2009, 7, 3156.
31. Sanjeevakumar, N.; Periasamy, M. Tetrahedron: Asymmetry 2009, 20, 1842.
32. Breuning, M.; Hein, D.; Steiner, M.; Gessner, V. H.; Strohmann, C. Chem. Eur. J.
2009, 15, 12764.
4.1.22. (3S,4S)-2-Methyl-4-nitrohexan-3-ol 5e21
Compound 5e was purified by silica gel column chromatogra-
phy (EtOAc/hexanes = 15:85) to afford a colorless oil, 67% yield,
61:39 syn/anti, 94% ee (syn). 1H NMR (400 MHz, CDCl3): d = 4.56–
4.42 (m, 1H), 3.83–3.60 (m, 1H), 2.40–2.20 (m, 1H), 2.10–2.00
(m, 1H), 1.92–1.63 (m, 2H), 1.05–0.90 (m, 9H). Enantiomeric excess
was determined by HPLC with a Chiralcel AD–H column (hexane/
33. Noole, A.; Lippur, K.; Metsala, A.; Lopp, M.; Kanger, T. J. Org. Chem. 2010, 75,
1313.
34. Arai, T.; Takashita, R.; Endo, Y.; Watanabe, M.; Yanagisawa, A. J. Org. Chem.
2008, 73, 4903.
35. Arai, T.; Taneda, Y.; Endo, Y. Chem. Commun. 2010, 46, 7936.
36. Steurer, M.; Bolm, C. J. Org. Chem. 2010, 75, 3301.
37. Blay, G.; Climent, E.; Fernandez, I.; Hernández-Olmos, V.; Pedro, J. R.
Tetrahedron: Asymmetry 2007, 18, 1603.
38. Blay, G.; Domingo, L. R.; Hernández-Olmos, V.; Pedro, J. R. Chem. Eur. J. 2008, 14,
4725.
isopropanol = 95:5, 1.0 mL/min, 208 nm), for syn-product, tmajor
8.4 min, tminor = 10.6 min.
=

Z.-L. Guo et al. / Tetrahedron: Asymmetry 22 (2011) 238–245
245
39. Gan, C.; Lai, G.; Zhang, Z.; Wang, Z.; Zhou, M. M. Tetrahedron: Asymmetry 2006,
17, 725.
49. Constable, E. C.; Zhang, G.; Housecroft, C. E.; Neuburger, M.; Schaffner, S.;
Woggon, W. D.; Zampese, J. A. New J. Chem. 2009, 33, 2166.
50. Trost, B. M.; Yeh, V. S. C. Angew. Chem., Int. Ed. 2002, 41, 861.
51. Trost, B. M.; Yeh, V. S. C.; Ito, H.; Bremeyer, N. Org. Lett. 2002, 4, 2621.
52. Palomo, C.; Oiarbide, M.; Laso, A. Angew. Chem., Int. Ed. 2005, 44, 3881.
53. Bulut, A.; Aslan, A.; Dogan, Ö. J. Org. Chem. 2008, 73, 7373.
54. Lu, G.; Li, X. S.; Zhou, Z. Y.; Chan, W. L.; Chan, A. S. C. Tetrahedron: Asymmetry
2001, 12, 2147.
55. Lu,G.;Kwong,F.Y.;Ruan,J.W.;Li,Y.M.;Chan,A.S.C.Chem.Eur.J.2006,12,4115.
56. Liu, C.; Guo, Z. L.; Weng, J.; Lu, G.; Chan, A. S. C. Chirality 2010, 22, 159.
57. Sasai, H.; Tokunaga, T.; Watanabe, S.; Suzuki, T.; Itoh, N.; Shibasaki, M. J. Org.
Chem. 1995, 60, 7388.
40. Xiong, Y.; Wang, F.; Huang, X.; Wen, Y.; Feng, X. Chem. Eur. J. 2007, 13, 829.
41. Jiang, J. J.; Shi, M. Tetrahedron: Asymmetry 2007, 18, 1376.
42. Colak, M.; Demirel, N. Tetrahedron: Asymmetry 2008, 19, 635.
43. Lai, G.; Wang, S.; Wang, Z. Tetrahedron: Asymmetry 2008, 19, 1813.
44. Guo, J.; Mao, J. Chirality 2009, 21, 619.
45. Xin, D.; Ma, Y.; He, F. Tetrahedron: Asymmetry 2010, 21, 333.
46. Qin, B.; Xiao, X.; Liu, X.; Huang, J.; Wen, Y.; Feng, X. J. Org. Chem. 2007, 72, 9323.
47. Mansawat, W.; Saengswang, I.; U-prasitwong, P.; Bhanthumnavin, W.;
Vilaivan, T. Tetrahedron Lett. 2007, 48, 4235.
48. Ha, W.; Shan, Z. Lett. Org. Chem. 2008, 5, 79.