Asymmetric Henry reaction catalyzed by Cu(II)-based chiral amino alcohol complexes with C2-symmetry

Article abstract of DOI:10.1016/j.tetasy.2016.06.018

A series of chiral amino alcohol ligands was prepared using commercial amino alcohols and phthalaldehydes. These ligands were used as catalysts in asymmetric Henry reactions in the presence of Cu(II) ions giving good yields (up to 97%) and enantiomeric excesses (ee, up to 98%). The DFT calculations showed the effect of the trans/cis configurations of the Cu-complexes on the origin of enantioselectivity. The easy catalyst preparation, mild reaction conditions, high yields and excellent enantioselectivities make these catalysts suitable for widespread use.

Full text of DOI:10.1016/j.tetasy.2016.06.018

Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric Henry reaction catalyzed by Cu(II)-based chiral amino
alcohol complexes with C2-symmetry
a
c
c
Gonghao Lu a, Fei Zheng a, Lei Wang a, Yuxin Guo a, Xue Li b, , Xianjun Cao , Cuiping Wang , Haijun Chi ,
⇑
Yan Dong c, Zhiqiang Zhang c,
⇑
a School of Chemical Engineering, University of Science and Technology Liaoning, 185 Qianshan Zhong Road, Anshan, Liaoning 114051, PR China
b School of Material and Metallurgy, University of Science and Technology Liaoning, 185 Qianshan Zhong Road, Anshan, Liaoning 114051, PR China
c Key Laboratory for Functional Material, Educational Department of Liaoning Province, University of Science and Technology Liaoning, Anshan, Liaoning 114051, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of chiral amino alcohol ligands was prepared using commercial amino alcohols and phthalalde-
hydes. These ligands were used as catalysts in asymmetric Henry reactions in the presence of Cu(II) ions
giving good yields (up to 97%) and enantiomeric excesses (ee, up to 98%). The DFT calculations showed
the effect of the trans/cis configurations of the Cu-complexes on the origin of enantioselectivity. The easy
catalyst preparation, mild reaction conditions, high yields and excellent enantioselectivities make these
catalysts suitable for widespread use.
Received 9 April 2016
Revised 13 June 2016
Accepted 15 June 2016
Available online xxxx
Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction
electivities [more than 90% enantiomeric excess (ee)]. However,
the preparations of these amino alcohol catalysts generally are
The Henry (nitroaldol) reaction is one of the most important
carbon–carbon bond forming reactions for the synthesis of
b-nitroalkanols,1 versatile intermediates in synthetic bifunctional
compounds, such as 1,2-amino alcohols,2 1,2-diamines,3 and
complicated processes or require the use of expensive chiral com-
pounds, which greatly limits their practical applications. Therefore,
it is necessary to further explore the application of simple and
inexpensive amino alcohols in asymmetric Henry reactions.
Recently, copper complex C2-symmetric ligands were reported to
promote the asymmetric Henry reaction in diamine18 and diol19
systems. This type of symmetry can reduce the number of possible
diastereomeric transition states for the chiral ligand.20 Our goal is
to develop bidentate C2-symmetric ligands to improve the catalytic
effect and function in the Henry reaction. The development of inex-
pensive, efficient and selective catalysts would be of widespread
interest.
We have designed and prepared a series of C2-symmetric
b-amino alcohol ligands from commercially available chiral amino
alcohols by simple steps. Herein, we present a highly enantioselec-
tive and practically useful Henry reaction for a variety of aldehydes
and nitromethane catalyzed by a newly developed chiral amino
alcohol ligand/Cu(OAc)2ꢀH2O complex.
a
-amino substituted carbonyl derivatives.4 These derivatives can
be used for the preparation of various pharmaceutical substances,5
whose enantiomeric purity is an important determinant of thera-
peutic effects.6 Therefore, many studies have focused on the iden-
tification of suitable catalysts for carrying out this reaction with
high yields and enantiocontrol.7 The first asymmetric Henry reac-
tion using rare earth metal alkoxides was reported by Shibasaki8
in 1992 and a variety of transition metal-catalyzed asymmetric
Henry reactions were subsequently reported.9 In particular, Cu(II)
complexes of a variety of bidentate10 and tridentate11 ligands were
recently developed with good results. Many copper catalytic sys-
tems have been developed for asymmetric Henry reactions with
chiral ligands, such as Schiff bases,12 diamines,13 bisoxazolines,14
aminopyridines,15 and others.
Since the initial work by Oguni et al., amino alcohol metal com-
plexes have received increased attention because of their diverse
applications.16 There are many reported examples of their applica-
tion in Henry reactions.17 In several cases, these amino alcohol
catalysts showed both good catalytic capability and good enantios-
2. Results and discussion
2.1. Synthesis of the ligands
Ligands were prepared via
between commercially available chiral b-amino alcohols,
lalaninol 1a or -phenylglycinol 1b, and the corresponding
a
one-pot, two-step reaction
L
-pheny-
⇑
Corresponding authors. Tel.: +86 412 5929931; fax: +86 412 5216902.
E-mail addresses: xli@ustl.edu.cn (X. Li), zhangzhiqiang@ustl.edu.cn (Z. Zhang).
L
http://dx.doi.org/10.1016/j.tetasy.2016.06.018
0957-4166/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Lu, G.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.06.018

2
G. Lu et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
R
Next, different copper salts were screened in order to improve
the enantioselectivity of the reaction in combination with ligand
6a and ethanol as the solvent (Table 1, entries 6–9). We deter-
mined that other copper salts were inferior to Cu(OAc)2ꢀH2O, which
slightly improved the enantioselectivity from 89% to 90% (Table 1,
entries 6). Since ligand 6b with Cu(OAc)2 only showed slightly
lower results than 6a (Table 1, entries 3, 4), 6b with Cu(OAc)2ꢀH2O
was also investigated. The results exhibited inferior performances
both in terms of yield and enantioselectivity compared to 6a
(Table 1, entries 10). Combining the convenience of the solvent
without further dryness, 6a with Cu(OAc)2ꢀH2O was the best cata-
lyst and was chosen for further study of the reaction parameters.
A base is usually added to promote the Henry reaction, and
therefore further investigated the effect of base on the reaction rate
and enantioselectivity. Although the observed reactivity could be
improved upon by adding smaller bases, the enantioselectivity lar-
gely decreased (Table 2, entries 2, 3). Additionally, both the reac-
tion rate and the enantioselectivity were considerably reduced
with bigger bases (Table 2, entries 4, 5). Therefore, none of tested
bases seemed ideal.
N
H
CHO
OH
5
2
OH
R
R
(1) AcOH
EtOH
OH
H
N
N
H
reflux
OHC
CHO
CHO
+
R
NH2
HO
6
(2) NaBH4
CH3OH
1
3
0°C - rt
OH
NH
R
OHC
N
H
OH
R
a, R = benzyl
b, R = phenyl
7
4
Scheme 1. One-pot syntheses of amino alcohol derivatives.
benzaldehyde 2, 1,4-phthalaldehyde 3 or 1,3-phthalaldehyde 4, as
shown in Scheme 1. Amino alcohols 1 firstly react with the aldehy-
des to form enamines, and the enamines are further reduced by
NaBH4 to give the target ligands. Five pure products 5, 6 and 7a
were successfully obtained with high yields. Unfortunately, we
were unable to obtain 7b using this method. When we carried
out the reaction of 1b and 4, most products resulted from the com-
pound of 1b reacting with one aldehyde group of 4. We also tested
the reaction of 1 with 1,2-phthalaldehyde and observed the similar
results, where only one aldehyde group of 1,2-phthalaldehyde
reacted because of steric hindrance.
The solvent can have an important influence on the activity of
the catalyst in the asymmetric reaction. Therefore, we next
employed different solvents to try to improve the reaction
(Table 2, entries 6–14). The results showed that protic solvents
(Table 2, entries
1 and 9–14) were superior to aprotic
solvents (Table 2, entries 6–8). Of the solvents tested, t-BuOH
was the best single solvent in terms of enantioselectivity. Consid-
ering the relatively high melting point of t-BuOH (25.7 °C), we next
examined a mixture of t-BuOH/EtOH as the solvent. When the
volume ratio of t-BuOH/EtOH was 1:10, a slight increase in
enantioselectivity was observed (Table 2, entry 13), compared with
the reaction using t-BuOH as a single solvent at a higher tempera-
ture. Increasing the amount of t-BuOH slightly decreased the yield
without any change in enantioselectivity (Table 2, entries 14).
The reaction enantioselectivity can be enhanced at lower tem-
peratures. In one example (Table 3, entry 2), when the reaction
was carried out at 10 °C, 90% yield and 96% ee were achieved,
2.2. Screening of the ligands
We first examined the Cu-catalyzed asymmetric Henry reaction
of p-nitrobenzaldehyde 8a (1 mmol) in the presence of 10 mol %
for 5 or 5 mol % for 6 and 7a amino alcohol ligand and 10 mol %
Cu(OAc)2 in 5 ml of dry ethanol at room temperature. Considering
that the coordination center of 5 was less than those of 6 and 7a,
the amount of ligand 5 was two times the amount of 6 and 7 to
guarantee the same amount of catalyst. The results are summa-
rized in Table 1. All of the tested ligands 5–7 showed good yields
(85–95%), but large differences in terms of enantioselectivity
(Table 1, entries 1–5). The most selective ligand 6a was selected
as a potential ligand for further studies.
Table 2
The effect of base and solvent on the asymmetric Henry reactiona
OH
6a (5 mol %)
CHO
NO2
Cu(OAc)2•H2O (10 mol %)
Table 1
CH3NO2
Optimization of the catalytic ligands 5, 6 and 7a and copper salts effect on the
solvent, rt, 24h
O2N
asymmetric Henry reactiona
O2N
9a
8a
OH
CHO
Entry
Solvent
Base
Yieldb (%)
eec (%)
5
6
7a
(10mol%), or (5 mol %)
NO2
Cu(I) or Cu(II) (10 mol %)
CH3NO2
1
2
3
4
EtOH
EtOH
EtOH
EtOH
89
98
95
85
90
46
64
75
O2N
EtOH, rt, 24h
O2N
(C2H5)3N
(PhCH2)3N
BnCH2N(Bn)2
8a
9a
Entryb
Metal
Ligand
Yieldc (%)
eed (%)
NBn2
5
EtOH
68
73
1
2
3
4
5
6
7
8
9
10
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
5a
5b
6a
6b
7a
6a
6a
6a
6a
6b
95
93
92
89
85
89
68
79
44
88
12
8
6
7
8
9
10
11d
12
13
14
THF
83
79
65
81
87
85
88
86
83
83
85
87
83
90
91
91
93
93
89
85
21
90
35
52
27
85
MeCN
CH2Cl2
MeOH
i-PrOH
t-BuOH
t-BuOH/EtOH (1:20 v/v)
t-BuOH/EtOH (1:10 v/v)
t-BuOH/EtOH (1:5 v/v)
Cu(OAc)2ꢀH2O
CuCl2
CuOAc
CuCl
Cu(OAc)2ꢀH2O
a
a
Reactions were performed with p-nitrobenzaldehyde (1 mmol), ligand (10 mol
Reactions were performed with p-nitrobenzaldehyde (1 mmol), 6a (5 mol %)
% for 5a and 5b, or 5 mol % for 6a, 6b and 7a) and copper salt (10 mol %), and
and Cu(OAc)2ꢀH2O (10 mol %), and nitromethane (10 mmol) in 5 ml of solvent for
nitromethane (10 mmol) in 5 ml of ethanol for 24 h.
24 h.
b
b
For entries 1–5, ethanol was dried over sodium and distilled before use.
Isolated yields after column chromatography.
Determined by HPLC with OD-H column.
Isolated yields after column chromatography.
Determined by HPLC with OD-H column.
c
c
d
d
Reaction was carried out at 30 °C.
Please cite this article in press as: Lu, G.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.06.018

G. Lu et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
3
Table 3
Table 4
The effect of the temperature and the amount of the solvent on the asymmetric Henry
Substrate scope of aldehydes and nitromethane in the asymmetric Henry reactiona
reactiona
6a
(5 mol %)
OH
Cu(OAc)2•H2O (10 mol %)
OH
NO2
R
CHO
CH3NO2
6a (5 mol %)
CHO
R
NO2
Cu(OAc)2•H2O (10 mol %)
t-BuOH/EtOH, 10°C
8
9
CH3NO2
O2N
solvent, rt, 24h
O2N
8a
9a
eec (%)
Entry
Aldehyde (R)
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
4-NO2C6H4 8a
3-NO2C6H4 8b
2-NO2C6H4 8c
C6H5 8d
4-CNC6H4 8e
4-CF3C6H4 8f
3-FC6H4 8g
4-BrC6H4 8h
4-ClC6H4 8i
2,4-diClC6H3 8j
4-Br-2-FC6H3 8k
4-HOCC6H4 8l
4-CH3OC6H4 8m
3-CH3OC6H4 8n
2-CH3OC6H4 8o
4-CH3C6H4 8p
2-CH3C6H4 8q
C6H5CH2 8r
45
45
45
48
48
48
48
48
48
48
60
45
60
48
48
48
48
24
24
24
24
24
90
88
93
82
85
91
74
81
74
82
77
85
72
88
75
83
77
94
97
93
86
90
96 (R)
94 (R)
98 (R)
95 (R)
97 (R)
95 (R)
93 (R)
96 (R)
96 (R)
97 (R)
97 (R)
96 (R)
89 (R)
94 (R)
98 (R)
95 (R)
98 (R)
94 (R)
92 (R)
94 (R)
97 (R)
95 (R)
Entry
Solvent (ml)
Temp (°C)
Time (h)
Yieldb (%)
1
2
3
4
5
t-BuOH/EtOH (5)
t-BuOH/EtOH (5)
t-BuOH/EtOH (5)
t-BuOH/EtOH (2)
EtOH (2)
rt
10
0
10
10
24
45
72
45
45
86
90
54
92
92
93
95
95
96
93
a
Reactions were performed with p-nitrobenzaldehyde (1 mmol), 6a (5 mol %)
and Cu(OAc)2ꢀH2O (10 mol %), and nitromethane (10 mmol) in t-BuOH/EtOH (1:10
9
10
11
12
13
14
15
16
17
18
19
20
21
22
v/v) at different temperature.
b
Isolated yields after column chromatography.
Determined by HPLC with OD-H column.
c
although a prolonged reaction time was required. Lowering the
temperature of the reaction to 0 °C resulted in a significant
decrease in the reaction rate with no obvious improvements in
the enantioselectivity (Table 3, entry 3). When the amount of sol-
vent was reduced to 2 ml, a slight increase in both the reactivity
and enantioselectivity was observed (Table 3, entry 4). Finally,
when the reaction was examined in ethanol alone under the opti-
mized reaction conditions (Table 3, entry 5), a slight decrease in
enantioselectivity was observed. Therefore, a mixed solvent of
t-BuOH/EtOH (1:10, v/v) was established as the optimal choice
for this catalytic system.
CH3CH2 8s
(CH3)2CH 8t
(CH3)3C 8u
Cyclohexyl 8v
a
Reactions were performed with the aldehyde (1 mmol) and nitromethane
(10 mmol) in 2 ml of t-BuOH/EtOH (1:10).
b
Isolated yield after column chromatography.
Determined by chiral HPLC.
c
When a b-amino alcohol forms a Cu(II) complex with a struc-
ture of a five-membered ring, trans- and/or cis-configurations likely
form. Generally, the trans-form is more stable than the cis-form
due to steric hindrance. However, the trans- and cis-forms for the
Cu(II)-complexes of ligand 5a have almost the same energy accord-
ing to the calculations (Table 5), hence there is almost no trans/cis-
selectivity for the formation of the ligand 5a–Cu(II) complex.
Therefore, the Cu(II)-complex of ligand 5a shows almost no cat-
alytic enantioselectivity. Ligand 6a with two equivalent Cu(II) will
generate three possible configurations [6a-I (trans, trans), 6a-II
(trans, cis) and 6a-III (cis, cis)]. The results of calculations indicate
that the energy of 6a-I is approximately 42 or 53 kJ/mol lower than
that of 6a-II or 6a-III, respectively. 6a-I is much more stable than
the other forms. Consequently, the Cu(II)-complex of 6a in the cat-
alytic system should be the trans/trans-form 6a-I.
The methylene groups on the nitrogen atoms are perpendicular
to the almost planar structure of the tetra-coordinated copper
complex. According to the model proposed by Evans,9a the most
effective transition state model positions places the nucleophile
(CH3NO2) perpendicular to the ligand plane and the electrophile
(aldehyde) is in the ligand plane. In our case, the CH3NO2 at the
axial position was fixed by hydrogen bonding with the N–H
group and the electrophile in the equatorial position was
oriented in the most appropriate way, thus allowing a si-face
attack. CH3NO2 attacked the si-face of the aldehyde. Thus,
catalyst 6a-I in the (trans, trans) configuration yields a product
with an (R)-configuration (Scheme 2).
2.3. Asymmetric Henry reaction to various aldehydes by ligand
6a
Using the optimized reaction conditions, we examined a variety
of aldehydes to determine the generality of the method. All of the
tested aromatic and aliphatic aldehydes produced the correspond-
ing (R)-enriched products with good yields of the isolated products
(72–97%) and excellent enantioselectivities (P89% ee) using the
amino alcohol 6a (Table 4). Stereoselectivities showed the little
influence of the electronic and steric character of substituents in
the aromatic ring, and the enantiomeric purities ranged from good
to high (Table 4, entries 1–17). Although the ortho-substituted aro-
matic aldehydes gave the corresponding products with higher
enantioselectivities due to their larger steric hindrances from the
ortho-groups (P97% ee, Table 4, entries 3, 10, 11, 15 and 17), the
para-substituted aldehydes gave comparable enantiomeric
excesses with ortho-substituted aldehydes. Aldehydes with elec-
tron-withdrawing substituents led to products with enantioselec-
tivities similar to aldehydes with electron-donating substituents.
Typically aliphatic aldehydes provided the corresponding
adducts with higher reactivities than aromatic aldehydes (Table 4,
entries 18–22). The obtained enantioselectivities were above 90%
for essentially all of the tested aliphatic aldehydes. In particular,
a-branched aliphatic aldehydes, such as pivalaldehyde, yielded
the product with excellent enantioselectivities of up to 97%
(Table 4, entry 21).
2.4. Theoretical mechanistic study
3. Conclusion
To rationalize the stereochemical outcome of the reaction, cal-
culations of the geometries of the complexes were fully optimized
at the B3LYP/6-31+G⁄ level,21 using the Gaussian03 program. The
optimal geometries and SCF energies are summarized in Table 5.
In conclusion, we have shown that a readily available amino
alcohol 6a and commercial Cu(OAc)2ꢀH2O formed a new practical
catalytic system that allows for a highly stereoselective Henry
reaction between aromatic aldehydes and nitromethane. Henry
Please cite this article in press as: Lu, G.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.06.018

Table 5
The optimal geometries and SCF energies
R2
N
R2
H
N
H
R1
H
R2
H
H
H
O
H
O
Cu(OAc)2
+
and/or
R1
AcO
trans
O
NH
R1
Cu
Cu
H
AcO
OAc
OAc
cis
6a-I
6a-II
6a-III
5a-I
5a-II
(trans, trans)
(cis, trans)
(cis, cis)
(trans)
(cis)
H
H
H
H
H
H
H
O
H
H
H
OAc
AcO
O
H
N
O
H
N
OAc
N
H
OAc
O
N
N
N
O
H
AcO
H
H
AcO
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Configuration
Cu
N
OAc
OAc
H
H
OAc
N
AcO
AcO
H
H
H
H
OAc
AcO
OAc
AcO
trans
AcO
O
O
O
H
H
cis
cis, trans
cis, cis
trans, trans
Optimal geometry
SCF energy (A.U.)
ꢁ5464.71344775
ꢁ5464.69728149
E6a-II ꢁ E6a-I = 42.5
ꢁ5464.69323993
E6a-III ꢁ E6a-I = 53.1
ꢁ2847.47755525
ꢁ2847.47727965
E5a-II ꢁ E5a-I = 0.7
D
E (kJ/mol)

G. Lu et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
5
O
N
Ph
Ph
Ph
O
Ph
H
Top
H
H
H
H
H
H
H
O
O
O
N
H
N
O
H
HO
O
N
O
H
H
O
H
O
N
H
O
O
CH3NO2
Bottom
O
Cu
Cu
N
Cu
N
Cu
O
O
O
O
O
O
O
CH3
CH3
O
CH3
CH3
Ph
H
H
H
TS (III)
TS (VI)
X
H
TS (IV)
TS (I)
O
N
H
PhCHO
CH3
O
Cu
O
O
Ph
Ph
X
X
O
O
H
H
N
H
H3
C
H
O
NO2
OH
O
N
O
H
H
6a-I
N
O
O
Cu
Cu
O
O
H
O
O
CH3
CH3
H
(R)-isomer
H
TS (V)
TS (II)
Scheme 2. Plausible transition state for the enantioselective Henry reaction.
adducts were formed in good yields and with high enantioselectiv-
ities under mild conditions. The DFT calculations revealed the role
of the trans-/cis-configuration effect in determining the enantiose-
lectivity of the catalysts. The easy catalyst preparations, mild reac-
tion conditions, high yields and excellent enantioselectivities
increase the potential application for this catalyst.
4.2.1. (S)-(ꢁ)-2-Benzylamino-3-phenylpropan-1-ol 5a
Colorless powder; yield 78.6%; mp: 105.2–109.5 °C; IR (cmꢁ1
,
KBr): 3462, 3252, 3025, 2928, 1601, 1571, 1487, 1065; 1H NMR
(500 MHz, CDCl3, ppm): d 7.15–7.32 (m, 10H), 3.82 (s, 2H), 3.66
(d, J = 10.5 Hz, 1H), 3.39 (dd, J1 = 10.5 Hz, J2 = 5.5 Hz, 1H), 3.00 (br
s, 3H), 2.88 (dd, J1 = 13.0 Hz, J2 = 6.5 Hz, 1H), 2.80 (dd,
J1 = 13.0 Hz, J2 = 7.5 Hz, 1H); 13C NMR (125 MHz, CDCl3, ppm): d
138.64, 138.05, 129.20, 128.64, 128.57, 128.32, 127.44, 126.57,
4. Experimental
4.1. General
62.19, 59.58, 50.89, 37.57; [
a]
25 = ꢁ23.8 (c 1.06, CH2Cl2).
D
4.2.2. (S)-(ꢁ)-2-Phenylamino-2-phenylethan-1-ol 5b
Colorless solid; yield 84.7%; mp: 94.2–95.8 °C; IR (cmꢁ1, KBr):
3374, 3256, 3020, 2926, 1600, 1552, 1485, 1070; 1H NMR
Unless otherwise specified, all reagents were purchased from
commercial suppliers and used without further purification. Reac-
tions were monitored by analytical thin-layer chromatography
(TLC) using silica gel 60 F 254 precoated glass plates (0.25 mm
thickness), which were visualized using UV light. Column chro-
matography was performed on silica gel (300–400 mesh). Petro-
leum ether used had bp 60–90 °C. Enantiomeric excesses (ee)
were determined by HPLC analysis using Chiralcel OD-H
(250 ꢂ 4.6 mm) with UV detector at 215 nm. NMR spectra were
recorded on Bruker Avance II (500 MHz). Internal standard (TMS
d = 0.00) and solvent peak (CHCl3 d = 77.0 or DMSO-d6 d = 39.5)
were used as chemical shift references. High resolution mass spec-
tra were recorded on Agilent 1260 LC–MS equipped with Agilent
6530 Q-TOF. Melting point was recorded by X-4 Optimelt (Shang-
hai optical instrument factory). The absolute configuration of
Henry products were assigned by comparison with data in
literature.
(500 MHz, CDCl3, ppm):
d 7.26–7.40 (m, 10H), 3.85 (dd,
J1 = 7.5 Hz, J2 = 3.5 Hz, 1H), 3.80 (d, J = 13 Hz, 1H), 3.72 (dd,
J1 = 11.0 Hz, J2 = 3.5 Hz, 1H), 3.60–3.63 (m, 2H), 2.85 (br s, 2H);
13C NMR (125 MHz, CDCl3, ppm):
d 139.57, 138.99, 128.80,
128.51, 128.45, 127.91, 127.43, 127.34, 66.46, 63.86, 50.95;
[a
]
D
25 = ꢁ26.2 (c 1.14, CH2Cl2).
4.2.3. (ꢁ)-N,N0-Bis[(2S)-1-hydroxy-3-phenylpropan-2-yl]-1,4-
xylylenediamine 6a
Colorless solid; yield 72.3%; mp: 150.9–151.8 °C; IR (cmꢁ1, KBr):
3472, 3232, 3029, 2922, 1602, 1591, 1491, 1076; 1H NMR
(500 MHz, DMSO-d6, ppm): d 7.26 (t, J = 7.5 Hz, 4H) 7.18 (m, 6H),
7.14 (s, 4H), 4.53 (t, J = 5.5 Hz, 2H), 3.70 (s, 4H), 3.25 (m, 2H),
2.61–2.71 (m, 6H), 1.83 (s, 2H); 13C NMR (125 MHz, DMSO-d6,
ppm) d: 139.69, 139.23, 129.17, 127.95, 127.48, 125.63, 62.29,
59.92, 50.25, 37.38; HRMS(ESI) for
427.2361 ([M+Na]+), found 427.2353;
CH2Cl2).
C26H32N2O2Na: calcd
4.2. General procedure for the preparation of 5–7
[a
]
D
25 = ꢁ48.7 (c 1.44,
In
a 100 mL round-bottomed flask, b-amino alcohols 1
(10 mmol), benzaldehyde 2 (1.06 g, 10 mmol) or phthalaldehydes
3 or 4, (0.67 g, 5 mmol) and one drop of acetic acid were dissolved
in ethanol (25 mL). The mixture was stirred and refluxed until TLC
revealed the reaction had proceeded to completion. The mixture
was cooled in an ice bath and methanol (5 mL) was added to the
mixture. After cooling to 0 °C, NaBH4 (1.0 g, 26 mmol) was added
in portions and then the mixture was stirred at ambient tempera-
ture until the reaction was complete. The reaction mixture was
adjusted to pH 8–9 by adding aqueous hydrochloric acid (1 N)
and further cooled in an ice bath for 0.5 h. Colorless powders were
collected by filtration, washed with water, and dried under
vacuum to obtain the desired products.
4.2.4. (ꢁ)-N,N0-Bis[(1S)-2-hydroxy-1-phenylethyl]-1,4-xylylene-
diamine 6b
Colorless solid; yield 91.4%; 114.0–117.0 °C; IR (cmꢁ1, KBr):
3384, 3259, 3018, 2929, 1599, 1549, 1481, 1078, 1043; 1H NMR
(500 MHz, DMSO-d6, ppm) d: 7.38 (d, J = 7.5 Hz, 4H), 7.33 (m,
4H), 7.25 (t, J = 8.0 Hz, 2H), 7.21 (s, 4H), 4.89 (dd, J1 = 5.5 Hz,
J2 = 5.0 Hz, 1H), 3.68 (m, 2H), 3.57 (m, 2H), 3.44 (s, 4H); 13C NMR
(125 MHz, DMSO-d6, ppm) d: 142.29, 139.54, 128.63, 128.19,
127.98, 127.37, 67.07, 64.45, 50.92; HRMS(ESI) for C24H28N2O2Na:
calcd 399.2048 ([M+Na]+), found 399.2056; [
CH2Cl2).
a]
25 = ꢁ51.6 (c 1.38,
D
Please cite this article in press as: Lu, G.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.06.018

6
G. Lu et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
4.2.5. (ꢁ)-N,N0-Bis[(2S)-1-hydroxy-3-phenylpropan-2-yl]-1,3-
xylylenediamine 7a
J = 8.0 Hz, 2H), 5.57 (m, 1H), 4.58 (dd, J1 = 9.0 Hz, J2 = 5.0 Hz, 2H),
3.03 (d, J = 4.0 Hz, 1H); 13C NMR (125 MHz, CDCl3, ppm): d
143.01, 132.80, 126.71, 118.12, 113.00, 86.60, 70.14; HPLC (Chiral-
cel OD-H, 85/15 n-hexane/i-PrOH, 0.8 mL/min, 215 nm), tr(major)
= 17.50 min, tr(minor) = 19.62 min.
Colorless solid; yield 93.6%, 110.9–120.0 °C; IR (cmꢁ1): 3454,
3302, 3024, 2937, 2925, 1604, 1491, 1460, 1059, 1032; 1H NMR
(500 MHz, DMSO-d6, ppm) d: 7.25 (t, J = 7.5 Hz, 2H), 7.18 (m, 7H),
7.12 (s, 1H), 7.08 (d, J = 7.5 Hz, 2H), 4.60 (t, J = 5.0 Hz, 2H), 3.69
(s, 4H), 2.63–2.72 (m, 6H), 1.82 (s, 2H); 13C NMR (125 MHz,
DMSO-d6, ppm) d: 141.39, 140.25, 129.73, 128.51, 128.26,
127.82, 126.46, 126.19, 62.80, 60.54, 51.06, 37.96; HRMS(ESI) for
4.3.6. (R)-2-Nitro-1-(4-trifluoromethylphenyl)ethanol 9f17c
Colorless oil; 91% yield; 95% ee; mp 88.2–90.6 °C; 1H NMR
(500 MHz, CDCl3, ppm):
d 7.70 (d, J = 8.1 Hz, 2H), 7.58 (d,
C
26H32N2O2Na: calcd 427.2361 ([M+Na]+), found 427.2353;
J = 8.0 Hz, 2H), 5.57 (dd, J1 = 9.3 Hz, J2 = 3.1 Hz, 1H), 4.66–4.52 (m,
2H), 2.88 (s, 1H); 13C NMR (125 MHz, CDCl3, ppm): d 142.03,
131.49, 131.10, 125.88, 80.86, 70.22; HPLC (Chiralcel OD-H,
[a
]
D
25 = ꢁ44.2 (c 1.33, CH2Cl2).
4.3. General procedure for the catalytic asymmetric Henry
reaction
85/15
n-hexane/i-PrOH,
0.8 mL/min,
215 nm),
tr(major)
= 12.64 min, tr(minor) = 15.57 min.
Ligand (10 mol % for 5, or 5 mol % for 6 and 7a), Cu(OAc)2ꢀH2O
(10 mol %) and solvent (2 mL) were added. The solution was stirred
for an hour to obtain a blue solution and then transferred to a bath
at the given reaction temperature. The aldehyde (1 mmol) and
nitroalkane (10 equiv) were added and the reaction mixture was
left stirring for the 24–72 h. After that the volatile compounds
were removed under reduced pressure, the residue was directly
purified on silica gel column eluting with petroleum ether/EtOAc
(10:1–5:1, v/v) to afford the corresponding product.
4.3.7. (R)-1-(3-Fluorophenyl)-2-nitroethanol 9g17h
Colorless oil; 74% yield; 93% ee; 1H NMR (500 MHz, CDCl3,
ppm): d 7.38 (m, 1H), 7.16 (dd, J1 = 2.0 Hz, J2 = 7.5 Hz, 2H), 7.06
(m, 1H), 5.48 (dd, J = 3.0 Hz, J2 = 9.5 Hz, 1H), 4.55 (m, 2H); 13C
NMR (125 MHz, CDCl3, ppm): d 163.12, 140.61, 130.69, 121.47,
115.91, 113.10, 80.95, 70.30; HPLC (Chiralcel OD-H, 85/15 n-hex-
ane/i-PrOH, 0.8 mL/min, 215 nm), tr(major) = 8.74 min, tr(minor)
= 9.27 min.
4.3.8. (R)-1-(4-Bromophenyl)-2-nitroethanol 9h13d
4.3.1. (R)-2-Nitro-1-(4-nitrophenyl)ethanol 9a13d
Yellow oil; 81% yield; 96% ee; 1H NMR (500 MHz, CDCl3, ppm): d
7.53 (d, J = 8.5 Hz, 2H), 7.27 (d, J = 8.5 Hz, 2H), 5.44 (m, 1H), 4.58
(dd, J1 = 9.5 Hz, J2 = 13.5 Hz, 1H), 4.50 (dd, J1 = 3.0 Hz, J2 = 13.5 Hz,
1H), 2.99 (d, J = 3.0 Hz, 1H); 13C NMR (125 MHz, CDCl3, ppm): d
137.11, 132.19, 127.60, 123.03, 80.89, 70.35; HPLC (Chiralcel OD-
H, 85/15 n-hexane/i-PrOH, 0.8 mL/min, 215 nm), tr(major)
= 13.82 min, tr(minor) = 17.12 min.
Pale yellow solid; 90% yield; 96% ee; mp 0.6–71.7 °C; 1H NMR
(500 MHz, CDCl3, ppm):
d 8.30 (d, J = 8.5 Hz, 2H), 7.65 (d,
J = 8.5 Hz, 2H), 5.63 (dd, J1 = 8.7 Hz, J2 = 3.7 Hz, 1H), 4.67–4.55 (m,
2H), 3.08 (br s, 1H); 13C NMR (125 MHz, CDCl3): d 148.22,
144.83, 126.94, 124.23, 80.57, 69.97; HPLC (Chiralcel OD-H,
85/15
n-hexane/i-PrOH,
1.0 mL/min,
215 nm),
tr(major)
= 19.35 min, tr(minor) = 24.65 min.
4.3.9. (R)-1-(4-Chlorophenyl)-2-nitroethanol 9i13d
4.3.2. (R)-2-Nitro-1-(3-nitrophenyl)ethanol 9b17h
Colorless oil; 74% yield; 96% ee; 1H NMR (500 MHz, CDCl3,
ppm): d 7.32–7.41 (m, 4H), 5.45 (d, J = 8.0 Hz, 1H), 4.47–4.60 (m,
2H), 2.96 (s, 1H); 13C NMR (125 MHz, CDCl3, ppm): d 136.62,
134.85, 129.26, 127.47, 82.34, 71.67; HPLC (Chiralcel OD-H,
Yellow solid, 88% yield; 94% ee; mp 62.4–64.8 °C; 1H NMR
(500 MHz, CDCl3, ppm): d 8.33 (s, 1H), 8.23 (d, J = 8.0 Hz, 1H),
7.78 (d, J = 8.0 Hz, 1H), 7.62 (dd, J1 = 8.0 Hz, J2 = 8.0 Hz, 1H), 5.62
(d, J = 7.5 Hz, 1H), 4.58–4.66 (m, 2H), 3.22 (br s, 1H); 13C NMR
(125 MHz, CDCl3, ppm): d 149.57, 141.12, 132.86, 131.04, 124.75,
122.06, 81.57, 70.78; HPLC (Chiralcel OD-H, 85/15 n-hexane/i-
PrOH, 0.8 mL/min, 215 nm), tr(major) = 19.74 min, tr(minor)
= 24.05 min.
85/15
n-hexane/i-PrOH,
0.8 mL/min,
215 nm),
tr(major)
= 13.03 min, tr(minor) = 16.42 min.
4.3.10. (R)-1-(2,4-Dichlorophenyl)-2-nitroethanol 9j13c
Colorless solid; 82% yield; 97% ee; mp 73.3–74.3 °C; 1H NMR
(500 MHz, CDCl3, ppm): 7.63 (d, J = 8.5 Hz, 1H), 7.43 (d,
d
4.3.3. (R)-2-Nitro-1-(2-nitrophenyl)ethanol 9c13b
J = 2.0 Hz, 1H), 7.36 (dd, J = 8.5 Hz, J2 = 2.0 Hz, 1H), 5.82 (m, 1H),
4.67 (dd, J1 = 13.5 Hz, J2 = 2.0 Hz, 1H), 4.44 (dd, J1 = 13.5 Hz,
J2 = 4.0 Hz, 1H), 3.04 (d, J = 4.0 Hz, 1H); 13C NMR (125 MHz, CDCl3,
ppm): d 135.30, 134.11, 132.11, 129.53, 128.59, 127.99, 79.05,
67.44; HPLC (Chiralcel OD-H, 85/15 n-hexane/i-PrOH, 0.8 mL/min,
215 nm), tr(major) = 9.86 min, tr(minor) = 11.81 min.
Colorless solid; 93% yield; 98% ee; mp 68.6–69.7 °C; 1H NMR
(500 MHz, CDCl3, ppm): d 8.09 (d, J = 7.5 Hz, 1H), 7.96 (d, J = 8 Hz,
1H), 7.76 (m, 1H), 7.57 (m, 1H), 6.06 (dd, J1 = 2.0 Hz, J2 = 9.0 Hz,
1H), 4.89 (dd, J1 = 2.0 Hz, J2 = 13.5 Hz, 1H), 4.57 (dd, J1 = 9.0 Hz,
J2 = 13.5 Hz, 1H), 3.16 (br s, 1H); 13C NMR (125 MHz, CDCl3,
ppm): d 135.24, 134.84, 129.60, 125.94, 80.95, 67.72; HPLC (Chiral-
cel OD-H, 85/15 n-hexane/i-PrOH, 0.8 mL/min, 215 nm), tr(major)
= 25.08 min, tr(minor) = 31.01 min.
4.3.11. (R)-1-(5-Bromo-2-fluorophenyl)-2-nitroethanol 9k
Wine-red oil; 77% yield; 97% ee; 1H NMR (500 MHz, CDCl3): d
7.74 (dd, J1 = 6.5 Hz, J2 = 2.0 Hz, 1H), 7.48 (m, 1H), 7.00 (dd,
J1 = 9.5 Hz, J2 = 9.0 Hz, 1H), 5.73 (dd, J1 = 9.0 Hz, J2 = 2.0 Hz, 1H),
4.60 (dd, J1 = 9.5 Hz, J2 = 2.5 Hz, 2H), 3.11 (br s, 1H); 13C NMR
(125 MHz, CDCl3, ppm): d 159.22, 157.26, 133.31, 130.70, 127.26,
117.52, 79.32, 64.89; HPLC (Chiralcel OD-H, 85/15 n-hexane/i-
PrOH, 0.8 mL/min, 215 nm), tr(major) = 15.48 min, tr(minor)
= 17.55 min.
4.3.4. (R)-2-Nitro-1-phenylethanol 9d13d
Colorless oil; 82% yield; 95% ee; 1H NMR (500 MHz, CDCl3,
ppm): d 7.36–7.20 (m, 5H), 5.33–5.26 (m, 1H), 4.46–4.40 (dd,
J1 = 13.1 Hz, J2 = 9.9 Hz, 1H), 4.36–4.32 (dd, J1 = 13.1 Hz,
J2 = 3.6 Hz, 1H), 3.07 (d, J = 3.6 Hz, 1H); 13C NMR (125 MHz, CDCl3,
ppm): d 138.33, 128.92, 128.81, 125.87, 81.20, 70.92; HPLC (Chiral-
cel OD-H, 85/15 n-hexane/i-PrOH, 0.8 mL/min, 215 nm), tr(major)
= 11.76 min, tr(minor) = 14.36 min.
4.3.12. (R)-1-(4-Formylphenyl)-2-nitroethanol 9l
Colorless solid; 85% yield; 96% ee; mp 58.3–60.5 °C; 1H NMR
(500 MHz, CDCl3): d 10.02 (s, 1H), 7.92 (d, J = 8 Hz, 1H), 7.61 (d,
J = 8 Hz, 1H), 5.57 (dd, J1 = 3.0 Hz, J2 = 9.0 Hz, 1H), 4.59 (m, 2H),
3.01 (br s, 1H); 13C NMR (125 MHz, CDCl3, ppm) d 191.55,
4.3.5. (R)-1-(4-Cyanophenyl)-2-nitroethanol 9e17h
Colorless solid; 85% yield; 97% ee; mp 88.2–90.6 °C; 1H NMR
(500 MHz, CDCl3, ppm):
d 7.73 (d, J = 8.0 Hz, 2H), 7.57 (d,
Please cite this article in press as: Lu, G.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.06.018

G. Lu et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
7
144.50, 136.74, 130.31, 126.60, 80.80, 70.48; HPLC (Chiralcel OD-H,
85/15 n-hexane/i-PrOH, 0.8 mL/min, 215 nm), tr(major)
= 18.57 min, tr(minor) = 21.12 min.
4.3.20. (R)-3-Methyl-1-nitrobutan-2-ol 9t13c
Colorless oil, 93% yield, 94% ee; 1H NMR (500 MHz, CDCl3,
ppm): 4.48 (dd, J1 = 13.0 Hz, J2 = 2.8 Hz, 1H), 4.41 (dd,
d
J1 = 13.0 Hz, J2 = 9.2 Hz, 1H), 4.14 (dd, J1 = 9.2 Hz, J2 = 2.8 Hz, 1H),
2.48 (br s, 1H), 1.77–1.85 (m, 1H), 1.01 (d, J = 6.8 Hz, 3H), 1.00 (d,
J = 5.6 Hz, 3H); 13C NMR (125 MHz, CDCl3, ppm): d 79.25, 73.36,
31.79, 18.40, 17.47; HPLC (Chiralcel OD-H, 98/2 n-hexane/iPrOH,
0.5 mL/min, UV 215 nm), tr(major) = 38.87 min, tr(minor)
= 45.76 min
4.3.13. (R)-1-(4-Methoxyphenyl)-2-nitroethanol 9m13d
Colorless oil; 72% yield; 89% ee; 1H NMR (500 MHz, CDCl3,
ppm): d 7.27 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 8.0 Hz, 2H), 5.45 (m,
1H), 4.72–4.60 (m, 1H), 4.29–4.54 (m, 1H), 3.81 (s, 3H), 2.92 (br
s, 1H); 13C NMR (125 MHz, CDCl3, ppm): d 159.98, 130.21,
127.26, 114.39, 81.22, 70.57, 55.21; HPLC (Chiralcel OD-H, 85/15
n-hexane/i-PrOH, 0.8 mL/min, 215 nm), tr(major) = 15.72 min,
tr(minor) = 19.73 min.
4.3.21. (R)-3,3-Dimethyl-1-nitrobutan-2-ol 9u14c
Pale yellow oil; 86% yield; 96% ee; 1H NMR (500 MHz, CDCl3,
ppm):
d 4.52 (dd, J1 = 13.2 Hz, J2 = 2.0 Hz, 1H), 4.35 (dd,
4.3.14. (R)-1-(3-Methoxyphenyl)-2-nitroethanol 9n17i
J1 = 13.2 Hz, J2 = 10.5 Hz, 1H), 4.03 (dd, J1 = 10.5 Hz, J2 = 2.0 Hz,
1H), 2.45 (br s, 1H), 0.98 (s, 9H); 13C NMR (125 MHz, CDCl3,
ppm): d 78.26, 76.19, 34.28, 25.60; HPLC (Chiralcel OD-H, 97/3
n-hexane/i-PrOH, 0.8 mL/min, 215 nm), tr(major) = 14.28 min,
tr(minor) = 16.96 min.
Colorless oil; 88% yield; 94% ee; 1H NMR (500 MHz, CDCl3,
ppm): d 7.30 (t, J = 8.5 Hz, 1H), 6.85–7.01 (m, 3H), 5.41 (dd,
J1 = 9.5 Hz, J2 = 3.0 Hz, 1H), 4.56 (dd, J1 = 16.5 Hz, J2 = 13.0 Hz, 2H),
3.81 (s, 3H), 3.07 (br s, 1H) ppm; 13C NMR (125 MHz, CDCl3,
ppm): d 160.04, 139.98, 130.07, 118.12, 114.40, 111.53, 81.36,
70.96, 55.46; HPLC (Chiralcel OD-H, 85/15 n-hexane/i-PrOH,
0.8 mL/min, 215 nm), tr(major) = 19.08 min, tr(minor) = 24.63 min.
4.3.22. (R)-1-Cyclohexyl-2-nitroethanol 9v14c
Colorless oil, 90% yield, 95% ee; 1H NMR (500 MHz, CDCl3): d
4.49 (dd, J1 = 13.2 Hz, J2 = 2.8 Hz, 1H), 4.42 (dd, J1 = 13.2 Hz,
J2 = 8.8 Hz, 1H), 4.10 (m, 1H), 2.40 (br s, 1H), 1.88–1.78 (m, 3H),
1.74–1.66 (m, 2H), 1.54–1.44 (m, 1H), 1.33–1.05 (m, 5H); 13C
NMR (100 MHz, CDCl3): d 79.35, 72.87, 41.47, 28.85, 28.98, 26.11.
HPLC (Chiralcel OD-H, 97/3 n-hexane/i-PrOH, 0.8 mL/min,
215 nm): tr(major) = 26.35 min, tr(minor) = 28.62 min.
4.3.15. (R)-1-(2-Methoxyphenyl)-2-nitroethanol 9o17i
Colorless oil; 75% yield; 98% ee; 1H NMR (500 MHz, CDCl3,
ppm):
d 7.30–7.48 (m, 2H), 6.87–7.08 (m, 2H), 5.61 (dd,
J1 = 9.5 Hz, J2 = 3.2 Hz, 1H), 4.51–4.73 (m, 2H), 3.90 (s, 3H), 3.06
(br s, 1H); 13C NMR (125 MHz, CDCl3, ppm): d 156.09, 129.90,
127.28, 126.12, 121.28, 110.64, 79.95, 67.87, 55.57; HPLC (Chiralcel
OD-H, 85/15 n-hexane/i-PrOH, 0.8 mL/min, 215 nm), tr(major)
= 12.47 min, tr(minor) = 15.76 min.
Acknowledgements
This research was supported by Natural Science Foundation of
Liaoning Province of China (2015020246) and the Foundation of
University of Science and Technology Liaoning (2015TD02).
4.3.16. (R)-1-(4-Methyphenyl)-2-nitroethanol 9p17i
Colorless oil; 83% yield; 95% ee; 1H NMR (500 MHz, CDCl3,
ppm): d 7.20 (d, J = 8.2 Hz, 2H), 7.10 (d, J = 8.2 Hz, 2H), 5.33–5.41
(dd, J1 = 9.6 Hz, J2 = 3.0 Hz, 1H), 4.51 (dd, J1 = 13.2 Hz, J2 = 9.6 Hz,
1H), 4.40 (dd, J1 = 13.2 Hz, J2 = 3.0 Hz, 1H), 2.75 (br s, 1H), 2.30
(s, 3H); 13C NMR (125 MHz, CDCl3, ppm): d = 138.84, 135.12,
129.56, 125.82, 81.15, 70.87, 21.16; HPLC (Chiralcel OD-H, 90/10
n-hexane/i-PrOH, 0.8 mL/min, 215 nm), tr(major) = 15.94 min,
tr(minor) = 19.31 min.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetasy.2016.06.
018.
References
4.3.17. (R)-1-(2-Methylphenyl)-2-nitroethanol 9q15c
Pale yellow oil; 77% yield; 98% ee; 1H NMR (500 MHz, CDCl3,
ppm): d 7.50–7.58 (m, 1H), 7.25–7.36 (m, 3H), 5.66–5.73 (m, 1H),
4.42–4.65 (2H, m), 3.05 (br s, 1H), 2.43 (s, 3H); 13C NMR
(100 MHz, CDCl3, ppm): d 136.24, 134.50, 130.90, 128.79, 126.84,
125.62, 80.21, 67.99, 18.93; HPLC (Chiralcel OD-H, 90/10 n-hex-
ane/i-PrOH, 0.8 mL/min, 215 nm), tr(major) = 11.05 min, tr(minor)
= 14.92 min.
1. (a) Henry, L.; Hebd, C. R. Seances Acad. Sci. 1895, 120, 1265–1267; (b) Poupart,
M. A.; Fazal, G.; Goulet, S.; Mar, L. T. J. Org. Chem. 1999, 64, 1356–1361; (c)
Ballini, R.; Petrini, M. Tetrahedron 2004, 60, 1017–1047.
2. (a) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835–875; (b)
Bergmeier, S. C. Tetrahedron 2000, 56, 2561–2576; (c) Bernardi, L.; Bonini, B. F.;
Dessole, G.; Fochi, M.; Comes-Franchini, M.; Gavioli, S.; Ricci, A. J. Org. Chem.
2003, 68, 1418–1425; (d) Nitabaru, T.; Kumagai, N.; Shibasaki, M. Tetrahedron
Lett. 2008, 49, 272–276.
3. (a) Tan, C.; Liu, X.; Wand, L.; Wang, J.; Feng, X. Org. Lett. 2008, 10, 5305–5308;
(b) Davis, T. A.; Johnston, J. N. Chem. Sci. 2011, 2, 1076–1079.
4. (a) Palomo, C.; Oiarbide, M.; Halder, R.; Laso, A.; Lopez, R. Angew. Chem., Int. Ed.
2006, 45, 117–120; (b) Kumaraswamy, G.; Pitchaiah, A. Helv. Chim. Acta 2011,
94, 1543–1550; (c) Knudsen, K. R.; Risgaard, T.; Nishiwaki, N.; Gothelf, K. V.;
Jorgensen, K. A. J. Am. Chem. Soc. 2001, 123, 5843–5844; (d) Weiner, B.;
Szymanski, W.; Janssen, D. B.; Minnaard, A. J.; Feringa, B. L. Chem. Soc. Rev.
2010, 39, 1656–1691.
5. (a) Das, A.; Kureshy, R. I.; Prathap, K. J.; Choudhary, M. K.; Rao, G. V. S.; Khan, N.
H.; Abdi, S. H. R.; Bajaj, H. C. Appl. Catal. A Gen. 2013, 459, 97–105; (b) Panov, I.;
Drabina, P.; Hanusek, J.; Sedlak, M. Synlett 2013, 1280–1282; (c) Rossi, S.;
Benaglia, M.; Porta, R.; Cotarca, L.; Maragni, P.; Verzini, M. Eur. J. Org. Chem.
2015, 2531–2537.
6. (a) Lednicer, D. Strategies of Organic Drug Synthesis and Design, 2nd ed.; John
Wiley & Sons: New Jersey, 2009; (b) Johnson, D.; Li, J. J. The Art of Drug
Synthesis; Wiley: New Jersey, 2007.
7. (a) Li, H.; Wang, B.; Deng, L. J. Am. Chem. Soc. 2006, 128, 732–733; (b) Taylor, M.
S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520–1543; (c) Palomo, C.;
Oiarbide, M.; Laso, A. Eur. J. Org. Chem. 2007, 2561–2574; (d) Vongvilai, P.;
Larsson, R.; Ramstroem, O. Adv. Synth. Catal. 2008, 350, 448–452.
8. (a) Sasai, H.; Suzuki, T.; Arai, S.; Arai, T.; Shibasaki, M. J. Am. Chem. Soc. 1992,
114, 4418–4420; (b) Sasai, H.; Tokunaga, T.; Watenabe, S.; Suzuki, T.; Itoh, N.;
Shibasaki, M. J. Org. Chem. 1995, 60, 7388–7389.
4.3.18. (R)-1-Nitro-3-phenylpropan-2-ol 9r12a
Yellow oil; 95% yield; 94% ee; 1H NMR (500 MHz, CDCl3, ppm): d
7.23–7.38 (m, 5H), 5.55–5.61 (m, 1H), 4.38–4.46 (m, 2H), 2.91 (dd,
J1 = 7.5 Hz, J2 = 13.8 Hz, 1H), 2.83 (dd, J1 = 6.0 Hz, J2 = 13.8 Hz, 1H);
13CNMR (125 MHz, CDCl3, ppm): d 135.89, 129.37, 128.90, 127.32,
79.68, 69.50, 40.42; HPLC (Chiralcel OD-H, 90/10 n-hexane/i-PrOH,
0.8 mL/min, 215 nm), tr(major) = 20.25 min, tr(minor) = 25.96 min.
4.3.19. (R)-1-Nitrobutan-2-ol 9s13c
Colorless oil, 97% yield, 92% ee; 1H NMR (500 MHz, CDCl3, ppm):
d 4.47 (dd, J1 = 13.2 Hz, J2 = 3.2 Hz, 1H), 4.40 (dd, J1 = 13.2 Hz,
J2 = 8.5 Hz, 1H), 4.20–4.30 (m, 1H), 2.62 (br s, 1H), 1.52–1.65 (m,
2H), 1.02 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3): d 80.44,
70.01, 26.91, 9.59 ppm; HPLC (Chiralcel OD-H, 96/4 n-hexane/
iPrOH, 0.5 mL/min, UV 215 nm), tr(major) = 36.78 min, tr(minor)
= 40.72 min.
Please cite this article in press as: Lu, G.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.06.018

8
G. Lu et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
9. Some selected papers: (a) Evans, D. A.; Seidel, D.; Rueping, M.; Lam, H. W.;
3061; (c) Ji, Y. Q.; Qi, G.; Judeh, Z. M. A. Tetrahedron: Asymmetry 2011, 22, 929–
935; (d) Blay, G.; Escamilla, A.; Hernandez-Olmos, V.; Pedro, J. R.; Sanz-Marco,
A. Chirality 2012, 24, 441–450.
Shaw, J. T.; Downey, C. W. J. Am. Chem. Soc. 2003, 125, 12692–12693; (b) Ooi, T.;
Doda, K.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 2054–2055; (c) Choudary, B.
M.; Ranganath, K. V. S.; Pal, U.; Kantam, M. L.; Sreedhar, B. J. Am. Chem. Soc.
2005, 127, 13167–13171; (d) Marcelli, T.; van der Haas, R. N. S.; van
Maarseveen, J. H.; Hiemstra, H. Angew. Chem., Int. Ed. 2006, 45, 929–931; (e)
Jiang, J. J.; Shi, M. Tetrahedron: Asymmetry 2007, 18, 1376–1382; (f) Kowalczyk,
R.; Sidorowicz, L.; Skarzewski, J. Tetrahedron: Asymmetry 2007, 18, 2581–2586;
(g) Mandal, T.; Samanta, S.; Zhao, C. G. Org. Lett. 2007, 9, 943–945; (h) Uraguchi,
D.; Sakaki, S.; Ooi, T. J. Am. Chem. Soc. 2007, 129, 12392–12393; (i) Liu, S. L.;
Wolf, C. Org. Lett. 2008, 10, 1831–1834; (j) Zheng, B.; Wang, M.; Li, Z. Y.; Bian, Q.
H.; Mao, J. Y.; Li, S. N.; Liu, S. Z.; Wang, M. G.; Zhong, J. C.; Guo, H. C. Tetrahedron:
Asymmetry 2011, 22, 1156–1160; (k) Holmquist, M.; Blay, G.; Muñoz, M. C.;
Pedro, J. R. Org. Lett. 2014, 16, 1204–1207; (l) Drabina, P.; Horakova, E.;
Ruzickova, Z.; Sedlak, M. Tetrahedron: Asymmetry 2015, 26, 141–147.
10. (a) Kang, S. W.; Ko, D. H.; Kim, K. H.; Ha, D. C. Org. Lett. 2003, 5, 4517–4519; (b)
Tao, D.; Chun, C. J. Fluorine Chem. 2013, 156, 183–186; (c) Bukuo, N.; Junpeng,
H. Tetrahedron Lett. 2013, 54, 462–465.
11. (a) Guo, J.; Mao, J. Chirality 2009, 21, 619–627; (c) Xu, K.; Lai, G.; Zha, Z.; Pan, S.;
Chen, H.; Wang, Z. Chem. Eur. J. 2012, 18, 12357–12363; (b) Zacharia, J. T.;
Tanaka, T.; Uesaka, Y.; Hayashi, M. Synthesis 2012, 44. 1625–1257.
12. (a) Lai, G. Y.; Wang, S. J.; Wang, Z. Y. Tetrahedron: Asymmetry 2008, 19, 1813–
1819; (b) Yang, W.; Du, D. M. Eur. J. Org. Chem. 2011, 1552–1556; (c) Wei, Y.;
Yao, L.; Zhang, B. L.; He, W.; Zhang, S. Y. Tetrahedron 2011, 67, 8552–8558; (d)
Yao, L.; Wei, Y.; Wang, P. G.; He, W.; Zhang, S. Y. Tetrahedron 2012, 68, 9119–
9124.
13. (a) Arai, T.; Watanabe, M.; Yanagisawa, A. Org. Lett. 2007, 9, 3595–3597; (b)
Noole, A.; Lippur, K.; Metsala, A.; Lopp, M.; Kanger, T. J. Org. Chem. 2010, 75,
1313–1316; (c) Zhou, Y. R.; Dong, J. F.; Zhang, F. L.; Gong, Y. F. J. Org. Chem.
2011, 76, 588–600; (d) Jin, W.; Li, X. C.; Wan, B. S. J. Org. Chem. 2011, 76, 484–
491; (e) Zhao, C. H.; Liu, F.; Gou, S. H. Tetrahedron: Asymmetry 2014, 25, 278–
283.
14. (a) Hargaden, G. C.; Guiry, P. J. Chem. Rev. 2009, 109, 2505–2550; (b) Spangler,
K. Y.; Wolf, C. Org. Lett. 2009, 11, 4724–4727; (c) Panov, I.; Drabina, P.;
Padelkova, Z.; Simunek, P.; Sedlak, M. J. Org. Chem. 2011, 76, 4787–4793; (d)
Holmquist, M.; Blay, G.; Pedro, J. R. Chem. Commun. 2014, 9309–9312.
15. (a) Blay, G.; Hernandez-Olmos, V.; Pedro, J. R. Chem. Commun. 2008, 4840–
4842; (b) Blay, G.; Hernandez-Olmos, V.; Pedro, J. R. Org. Lett. 2010, 12, 3058–
16. (a) Oguni, N.; Omi, T. Tetrahedron Lett. 1984, 25, 2823–2824; (b) Zhao, G.; Li, X.
G.; Wang, R. Tetrahedron: Asymmetry 2001, 12, 399–403; (c) Lu, J.; Xu, X. N.;
Wang, S. Z.; Wang, C. D.; Hu, Y. F.; Hu, H. W. J. Chem. Soc., Perkin Trans. 1 2002,
2900–2903; (d) Bisai, A.; Singh, P. K.; Singh, V. K. Tetrahedron 2007, 63, 598–
602; (e) Martins, J. E. D.; Wills, M. Tetrahedron: Asymmetry 2008, 19, 1250–
1255; (f) Mao, J. Synth. Commun. 2009, 39, 3710–3721.
17. (a) Zhong, Y. W.; Tian, P.; Lin, G. Q. Tetrahedron: Asymmetry 2004, 15, 771–776;
(b) Palomo, C.; Oiarbide, M.; Laso, A. Angew. Chem., Int. Ed. 2005, 44, 3881–
3884; (c) Bulut, A.; Aslan, A.; Dogan, O. J. Org. Chem. 2008, 73, 7373–7375; (d)
Kim, H. Y.; Oh, K. Org. Lett. 2009, 11, 5682–5685; (e) Mayani, V. J.; Abdi, S. H. R.;
Kureshy, R. I.; Khan, N. H.; Das, A.; Bajaj, H. C. J. Org. Chem. 2010, 75, 6191–
6195; (f) Guo, Z. L.; Zhong, S.; Li, Y. B.; Lu, G. Tetrahedron: Asymmetry 2011, 22,
238–245; (g) Zheng, B.; Wang, M.; Li, Z. Y.; Bian, Q. H.; Mao, J. Y.; Li, S. N.; Liu, S.
Z.; Wang, M. G.; Zhong, J. C.; Guo, H. C. Tetrahedron: Asymmetry 2011, 22, 1156–
1160; (h) Qin, D. D.; Lai, W. H.; Hu, D.; Chen, Z.; Wu, A. A.; Ruan, Y. P.; Zhou, Z.
H.; Chen, H. B. Chem. Eur. J. 2012, 18, 10515–10518; (i) Xu, F.; Yan, L.; Lei, C.;
Zhao, H.; Li, G. L. Tetrahedron: Asymmetry 2015, 26, 338–343; (j) Xu, F.; Lei, C.;
Yan, L.; Tu, J. X.; Li, G. Q. Chirality 2015, 27, 761–765.
18. (a) Arai, T.; Watanabe, M.; Fujiwara, A.; Yokoyama, N.; Yanagisawa, A. Angew.
Chem., Int. Ed. 2006, 45, 5978–5981; (b) Bandini, M.; Piccinelli, F.; Tommasi, S.;
Umani-Ronchi, A.; Ventrici, C. Chem. Commun. 2007, 616–618; (c) Kowalczyk,
R.; Sidorowicz, L.; Skarzewski, J. Tetrahedron: Asymmetry 2008, 19, 2310–2315;
(d) Kowalczyk, R.; Skar_zewski, J. Tetrahedron: Asymmetry 2009, 20, 2467–
2473; (e) Zhang, G.; Yashima, E.; Woggon, W. D. Adv. Synth. Catal. 2009, 351,
1255–1262; (f) Xiong, Y.; Wang, F.; Huang, X.; Wen, Y.; Feng, X. Chem. Eur. J.
2007, 13, 829–833; (g) Jin, W.; Li, X.; Huang, Y.; Wu, F.; Wan, B. Chem. Eur. J.
2010, 16, 8259–8261.
19. (a) Balsells, J.; Davis, J. T.; Carroll, P.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124,
10336–10348; (b) Gok, Y.; Kuloglu, S.; Gok, H. Z.; Kekec, L. Appl. Organomet.
Chem. 2014, 28, 835–838; (c) Gok, Y.; Kekec, L. Tetrahedron Lett. 2014, 55,
2727–2729.
20. (a) Whitesell, J. Chem. Rev. 1989, 89, 1581–1590; (b) Halm, C.; Kurth, M. J.
Angew. Chem., Int. Ed. 1998, 37, 510–512.
21. Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652.
Please cite this article in press as: Lu, G.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.06.018