BINOL-quinine-squaramides as efficient organocatalysts for the asymmetric Michael addition of 2-hydroxy-1,4-naphthoquinone to nitroalkenes

Article abstract of DOI:10.1016/j.tetasy.2013.11.019

A set of BINOL-quinine-squaramides were synthesized, and then used as organocatalysts to promote the catalytic enantioselective Michael addition reaction of 2-hydroxy-1,4-naphthoquinone to nitroalkenes with excellent yields and ees (up to 99% yield and 93

Full text of DOI:10.1016/j.tetasy.2013.11.019

Tetrahedron: Asymmetry 25 (2014) 181–186
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
BINOL–quinine–squaramides as efficient organocatalysts for the
asymmetric Michael addition of 2-hydroxy-1,4-naphthoquinone
to nitroalkenes
b
b,
Enshan Zhou a, , Bin Liu , Chune Dong
⇑
⇑
a Baoji Vocational Technology College, Baoji 721013, Shaanxi, China
b Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan
430071, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 October 2013
Accepted 27 November 2013
A set of BINOL–quinine–squaramides were synthesized, and then used as organocatalysts to promote the
catalytic enantioselective Michael addition reaction of 2-hydroxy-1,4-naphthoquinone to nitroalkenes
with excellent yields and ees (up to 99% yield and 93% ee) at low catalyst loading (0.5 mol %).
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
to nitroalkenes. Given the fact that chiral naphthoquinone deriva-
tives possess biological properties and potential application in
Asymmetric organic catalysis has experienced remarkable pro-
gress over the last decade.1 Many organocatalysts have been devel-
oped, which can be used to catalyze a variety of asymmetric
reactions.2 Among these, chiral squaramides and their derivatives,
developed by Rawal et al. as highly efficient organocatalysts in the
asymmetric Michael addition reactions,3 have been investigated
intensively and a number of asymmetric transformations have
been accomplished due to their unique structures.4 For example,
squaramide-based organocatalysts have been used in the kinetic
resolution of azalactones,5 Friedel–Crafts reactions of indole with
sulfonyl imines,6 Diels–Alder reactions,7 and enantioselective
Michael addition reactions of coumarin to ketoesters.8
Recently, Du et al. reported on the first thiourea and squaramide
catalyzed enantioselective Michael addition reaction of 2-hydroxy-
1,4-naphthoquinones to nitroalkenes.9 Both catalysts were highly
effective to give the desired products in excellent yields and ee
values. More recently, Pericàs et al. developed a recyclable polysty-
rene supported bifunctional squaramide organocatalyst, which can
promote the Michael addition of 2-hydroxy-1,4-naphthoquinones
to nitroalkenes and be adopted to continuous flow operations.10
As part of our continuing efforts to develop novel chiral
squaramide organocatalysts and their application in asymmetric
transformations,11 we have recently introduced the BINOL–
quinine–squaramide (BQS) as the best catalyst for the asymmetric
Michael addition of nitroalkenes to 1,3-dicarbonyl compounds. We
reasoned that this BINOL derived squaramide could be robust
toward the Michael addition of 2-hydroxy-1,4-naphthoquinones
medicinal chemistry,12 we embarked on the idea of investigating
the catalytic synthesis of chiral naphthoquinone compounds.
Herein we report the BINOL–quinine–squaramides (BQS) as multi-
ple H-bond donor organocatalysts for the asymmetric Michael
addition of 2-hydroxy-1,4-naphthoquinones to nitroalkenes to give
the desired products in excellent yields and enantioselectivities. A
series of chiral nitroalkanes were prepared with up to 93% ee.
2. Results and discussion
Organocatalysts 1a–e were obtained via a four-step procedure
according to previous methods.11e We began our investigation by
examining the Michael addition of 2-hydroxy-1,4-naphthoquinone
2 to nitroalkene 3a catalyzed by squaramide 1a (Scheme 1).
Using 3 mol % of 1a, the reaction turned out to be both rapid
and clean in methylene chloride (Table 1, entry 1). Under the same
reaction conditions, catalyst 1b and 1c also gave good enantiose-
lectivity. In contrast, the MOM-protected squaramide 1d gave
product 4a in lower yield and ee value (entry 4). Catalyst 1a proved
to be the most promising candidate for this transformation. The
results indicated the binaphthyl hydroxy group might serve as an
additional H-bond donor and play an important role in the
reaction. Simply changing the solvent from CH2Cl2 to CH3OH dra-
matically decreased the ee to 64% (entry 6). Other solvents, such
as CH3CN, toluene and ethanol were screened. Among them,
CH2Cl2 gave the best results. Finally decreasing the loading of 1a
to 0.5 mol % further increased the enantioselectivity (91% ee, entry
12) (see Table 1).
With the optimized conditions in hand, we next turned our
attention to the examination of the scope and limitations of the
⇑
Corresponding authors. Tel.: +86 27 68759586; fax: +86 27 68759850.
E-mail address: cdong@whu.edu.cn (C. Dong).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.11.019

182
E. Zhou et al. / Tetrahedron: Asymmetry 25 (2014) 181–186
N
O
O
N
O
O
OMe
H
N
N
H
N
H
OMe
O
O
H
N
H
N
H
N
OH
OH
N
H
OH
OH
N
H
N
H
N
OH
OH
1b
1a
N
N
O
O
O
O
1c
OMe
OMe
H
H
N
H
N
H
N
H
N
H
N
N
O
O
O
O
OH
OH
1e
1d
Scheme 1. Squaramide organocatalysts 1a–e.
Table 1
Optimization of the reaction conditions for the asymmetric Michael addition of 2 to 3aa
O
O
NO2
NO2
Cat
Solvent, rt. 24 h
*
+
OH
OH
O
O
3a
4a
2
Entry
Cat.
Loading (%)
Solvent
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1a
1a
1a
1a
1a
1a
1a
3
3
3
3
3
3
3
3
3
2
1
0.5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeOH
EtOH
CH3CN
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
99
96
93
91
95
88
81
94
92
98
99
99
89
87
84
80
83
64
74
78
86
90
90
91
9
10
11
12
a
Reaction conditions: unless otherwise noted, 2-hydroxy-1,4-naphthoquinone 2 (0.2 mmoL) was added to the agitated solution of nitroolefin 3a (0.2 mmoL) and catalysts
1a–1e in 1 mL of solvent at room temperature for 24 h.
b
Isolated yield.
c
Determined by HPLC analysis using a chiralpak AS-H column.
reaction of 2-hydroxy-1,4-naphthoquinone 2 with various nitro-
olefins 3. The results are summarized in Table 2. We found that a
wide range of nitroolefins reacted smoothly with 2, to afford the
corresponding Michael adducts in up to 99% yield and with up to
93% ee (Table 2, entries 1–16). The reaction tolerates a large sub-
strate scope within the aromatic nitroalkenes, not only electron
donating but also electron withdrawing substituted aromatic
nitroalkenes, and all gave the products with high yield and with
good to high ee value (Table 2, entries 1–12). Heteroaromatic nitro-
alkenes, such as 3m and 3n, worked well under the optimal condi-
tions, affording the desired products in high yields and 88% ee
value, respectively (Table 2, entries 13 and 14). When aliphatic
nitroalkenes were used, not only n-heptyl substituted but also
cyclohexyl nitroolefins were all tolerated, and gave the products
in high yields (94–97%) and with good to high ee values
(87–93%) (Table 2, entries 15–16), in which the linear aliphatic
nitroalkene 3o gave the best ee so far. The absolute configuration
of product 4g was determined to be (S) on the basis of X-ray
crystallographic analysis (Fig. 1).13
Furthermore, the recyclability of our catalyst 1a in the Michael
addition of 2 with 3a was also evaluated. From the results in
Table 3, it can be seen that our catalyst 1a can be easily recovered

E. Zhou et al. / Tetrahedron: Asymmetry 25 (2014) 181–186
183
Table 2
The asymmetric Michael addition of 2-hydroxy-1,4-naphthoquinone 2 to nitroalkenes 3 catalyzed by catalyst 1aa
O
O
O
R
NO2
0.5 mol% 1a
NO2
+
R
OH
OH
DCM, rt. 24 h
O
3
2
4
Entry
3
4
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
R = Ph 3a
R = 2-OH-Ph 3b
R = 4-MeO-Ph 3c
R = 4-OH-3-MeO-Ph 3d
R = 2-Cl-Ph 3e
R = 2-Br-Ph 3f
R = 4-F-Ph 3g
R = 4-Cl-Ph 3h
R = 4-Br-Ph 3i
R = 2,4-Cl-Ph 3j
R = 4-CN-Ph 3k
R = 4-CF3-Ph 3l
R = 2-furyl 3m
R = 2-thienyl 3n
R = n-hexyl 3o
R = cyclohexyl 3p
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
99
84
95
81
97
96
91
94
95
95
86
94
97
95
94
97
91
84
92
88
87
85
90
79
86
87
87
88
88
88
87
93
9
10
11
12
13
14
15
16
a
Reaction conditions: 2-hydroxy-1,4-naphthoquinone 2 (0.2 mmoL) was added to an agitated solution of nitroolefin 3 (0.2 mmoL)
and catalyst 1a in 1 mL of DCM at room temperature for 24 h.
b
Isolated yield.
c
Determined by HPLC analysis using chiralpak AS-H, chiralcel OJ-H or chiralpak AD-H columns.
due to its poor solubility; the catalyst still retained its high activity
and enantioselectivity. After three cycles, the recovery rate and
enantioselectivity were still quite good (96% yield and 91% ee).
Compared to the best catalyst reported in the literature,9b under
the same reaction conditions, the recovery rate decreased to 64%
after 2 cycles. Moreover, the catalyst needs further purification
by chromatography before the next cycle.
into (S)-3-phenyl-2,3-dihydro-1H-benzo-indole-4,9-dione
good yield without a loss of the enantiomeric purity.
5
in
4. Experimental
4.1. Materials and methods
To further illustrate the synthetic potential of this methodology,
the synthesis of (S)-3-phenyl-2,3-dihydro-1H-benzo-indole-4,9-
dione 5 was performed. As shown in Scheme 2, the asymmetric
Michael addition product 4a were treated with Pd/C in methanol
under a hydrogen atmosphere to generate 5 in 39% yield and
without a loss in enantiomeric purity.
Unless otherwise noted, dichloromethane was dried over CaH2
and distilled prior to use. Reactions were monitored by thin layer
chromatography (TLC) and column chromatography purifications
were performed using 230–400 mesh silica gel. Unless otherwise
noted, all NMR spectra were recorded using CDCl3 as the solvent
with reference to residual CHCl3 (1H at 7.26 ppm and 13C at
O
O
O
O
NO2
NH2
H2, Pd/C
MeOH, rt, 48 h
OH
N
H
OH
O
O
4a
(91% ee)
5
Scheme 2. Synthesis of cyclized compound 5.
77.0 ppm). Melting points were obtained on a micro-melting appa-
ratus and are uncorrected. Ees were determined by HPLC analysis
using a SHIMADZU Series instrument with Daicel Chiralpak AD-H
or Chiralpak AS-H or Chiralpak OJ-H columns, as indicated. The race-
mic samples were prepared using Et3N as the catalyst. The catalyst
1a–1f was prepared according to our previous work.11e Compounds
4a–d,14 4f–i,14 4l–p,14 and 4e9b were known in the literature.
3. Conclusions
We have developed BINOL–quinine–squaramides that cata-
lyzed the asymmetric Michael addition reactions of 2-hydroxy-
1,4-naphthoquinones to nitroalkenes at a low catalyst loading.
The desired products were formed in excellent yields and ees (up
to 99% yield and 93% ee). The Michael adduct 4a was transformed

184
E. Zhou et al. / Tetrahedron: Asymmetry 25 (2014) 181–186
Figure 1. X-ray crystal structure of 4g.
Table 3
The recyclability of catalyst 1a in the Michael addition of 2 to 3aa
O
O
NO2
NO2
0.5 mol% 1a
*
+
DCM, rt. 24 h
OH
OH
O
O
3a
2
4a
Cycle
Recovery rate 1a (%)
Yieldb (%)
eec (%)
1
2
3
4
92
91
89
87
98
97
96
96
91
91
91
90
a
Reaction conditions: unless otherwise noted, 2-hydroxy-1,4-naphthoquinone 2 (0.6 mmoL) was added
to an agitated solution of nitroolefin 3 (0.6 mmoL) and catalyst 1a in 3 mL of DCM at room temperature for
24 h.
b
Isolated yield.
c
Determined by HPLC analysis using a chiralpak AS-H column.

E. Zhou et al. / Tetrahedron: Asymmetry 25 (2014) 181–186
185
4.2. General procedure for the asymmetric Michael addition
reaction
4g: orange solid, 91% yield, mp 162–164 °C. 1H NMR (400 MHz,
CDCl3) d 8.11 (d, J = 8.0 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.80–7.76
(m, 1H), 7.72–7.68 (m, 1H), 7.50–7.41 (m, 2H), 7.00 (t, J = 8.0 Hz,
2H), 5.40 (dd, J = 12.0, 8.0 Hz, 1H), 5.33–5.26 (m, 1H), 5.16 (dd,
J = 12.0, 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) d 183.7, 181.0,
163.4, 161.0, 153.2, 135.5, 133.4, 132.5, 130.0, 129.9, 128.9,
127.2, 126.4, 120.6, 116.0, 115.7, 76.4, 39.0. Chiralpak AS-H column
(250 Â 4.6 mm), 10% i-PrOH/hexane; 1.0 mL/min, 254 nm;
tmajor = 35.0 min, tminor = 41.8 min, ee = 90%.
In a 10 mL round-bottomed flask, 2-hydroxy-1,4-naphthoqui-
none 2 (0.2 mmol) was added to an agitated solution of nitroolefin
3 (0.2 mmol) and catalyst 1a (0.7 mg) in 1 mL of dichloromethane
at room temperature. After 24 h, the reaction was monitored by
TLC, and then the mixture was concentrated and purified by silica
gel column chromatography to give the pure product 4.
4a: orange solid, 99% yield, mp 156–158 °C. 1H NMR (400 MHz,
CDCl3) d 8.12 (d, J = 8.0 Hz, 1H), d 8.07 (d, J = 8.0 Hz, 1H), 7.76 (t,
J = 8.0 Hz, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.47 (d, J = 4.0 Hz, 2H), 7.32
(t, J = 8.0 Hz, 2H), 7.28–7.24 (m, 1H), 5.48 (dd, J = 12.0, 8.0 Hz,
1H), 5.34–5.28 (m, 1H), 5.17–5.12 (m, 1H). 13C NMR (100 MHz,
CDCl3) d 183.7, 181.1, 153.2, 137.5, 135.4, 133.3, 132.6, 129.0,
128.3, 127.8, 127.2, 126.3, 120.8, 76.3, 39.6. Chiralpak AS-H column
(250 Â 4.6 mm), 10% i-PrOH/hexane; 1.0 mL/min, 254 nm;
tmajor = 26.2 min, tminor = 29.5 min, ee = 91%.
4h: orange solid, 94% yield, mp 191–193 °C. 1H NMR (400 MHz,
CDCl3) d 8.12 (d, J = 8.0 Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.79 (t,
J = 8.0 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 2H),
7.30–7.25 (m, 2H), 5.39 (dd, J = 12.0, 8.0 Hz, 1H), 5.33–5.25 (m,
1H), 5.16 (dd, J = 12.0, 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) d
183.6, 181.0, 153.2, 136.0, 135.5, 133.8, 133.4, 132.5, 129.6,
129.1, 128.9, 127.2, 126.4, 120.3, 76.1, 39.0. Chiralpak OJ-H column
(250 Â 4.6 mm), 30% i-PrOH/hexane; 1.0 mL/min, 254 nm;
tmajor = 31.7 min, tminor = 17.6 min, ee = 79%.
4b: orange solid, 85% yield, mp 162–164 °C. 1H NMR (400 MHz,
CDCl3) d 8.08 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.76–7.69
(m, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.31–7.29 (m, 1H), 7.15–7.06 (m,
1H), 6.90–6.79 (m, 2H), 5.55 (dd, J = 12.0, 8.0 Hz, 1H), 5.35 (dd,
J = 8.0, 4.0 Hz, 1H), 4.97 (dd, J = 12.0, 8.0 Hz, 1H). 13C NMR
(100 MHz, CDCl3) d 183.7, 181.1, 152.8, 152.7, 134.6, 132.8,
131.3, 128.5, 127.9, 127.3, 126.5, 125.6, 122.3, 120.2, 119.4,
117.1, 74.2, 32.2. Chiralpak OJ-H column (250 Â 4.6 mm), 30%
4i: orange solid, 95% yield, mp 45–47 °C. 1H NMR (400 MHz,
CDCl3) d 8.12 (d, J = 8.0 Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.81–7.76
(m, 1H), 7.72–7.69 (m, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.35 (d,
J = 8.0 Hz, 2H), 5.39 (dd, J = 12.0, 8.0 Hz, 1H), 5.32–5.22 (m, 1H),
5.16 (dd, J = 12.0, 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) d 183.6,
181.0, 153.2, 152.4, 140.1, 136.5, 135.5, 133.4, 132.5, 132.1,
130.0, 128.9, 127.2, 126.4, 121.9, 120.2, 76.0, 39.1. Chiralpak OJ-H
column (250 Â 4.6 mm), 30% i-PrOH/hexane; 0.8 mL/min, 254 nm;
tmajor = 50.5 min, tminor = 26.7 min, ee = 86%.
i-PrOH/hexane; 1.0 mL/min, 254 nm; tmajor = 38.2 min, tminor
=
21.9 min, ee = 84%.
4j: orange oil, 94% yield. 1H NMR (400 MHz, CDCl3) d 8.13–8.07
(m, 2H), 7.81–7.77 (m, 1H), 7.74–7.70 (m, 1H), 7.43–7.41 (m, 2H),
7.22–7.20 (m, 1H), 5.69–5.65 (m, 1H), 5.38–5.32 (m, 1H), 5.00–4.95
(m, 1H). 13C NMR (100 MHz, CDCl3) d 183.6, 180.8, 154.2, 135.6,
134.8, 134.3, 133.4, 133.2, 132.6, 130.4, 129.9, 128.9, 127.5,
127.3, 126.5, 118.8, 74.8, 36.6. Chiralpak OJ-H column
(250 Â 4.6 mm), 30% i-PrOH/hexane; 1.0 mL/min, 254 nm;
tmajor = 22.4 min, tminor = 14.5 min, ee = 87%.
4c: orange solid, 95% yield, mp 168–170 °C. 1H NMR
(400 MHz, CDCl3) d 8.11 (d, J = 8.0 Hz, 1H), 8.06 (d, J = 8.0 Hz,
1H),7.76 (t, J = 8.0 Hz, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.39 (d,
J = 8.0 Hz, 2H), 6.84 (d, J = 8.0 Hz, 2H), 5.44 (dd, J = 12.0, 8.0 Hz,
1H), 5.26 (dd, J = 12.0, 8.0 Hz, 1H), 5.12 (dd, J = 12.0, 8.0 Hz, 1H),
3.76 (s, 3H). 13C NMR (100 MHz, CDCl3) d 183.7, 181.2, 153.2,
137.5, 135.4, 133.3, 132.6, 129.0, 128.3, 127.8, 127.2, 126.3,
120.8, 76.3, 39.6. Chiralpak AS-H column (250 Â 4.6 mm), 20%
i-PrOH/hexane; 0.8 mL/min, 254 nm; tmajor = 44.3 min, tminor = 77.
7 min, ee = 92%.
4k: orange solid, 86% yield, mp 144–146 °C. 1H NMR (400 MHz,
CDCl3) d 8.04 (d, J = 8.0 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.73 (t,
J = 8.0 Hz, 1H), 7.67–7.62 (m, 1H), 7.58–7.48 (m, 4H), 5.34–5.23
(m, 2H), 5.22–5.15 (m, 1H). 13C NMR (100 MHz, CDCl3) d 183.5,
180.7, 153.6, 142.9, 135.7, 133.6, 132.7, 132.4, 129.1, 128.9,
127.3, 126.6, 119.5, 118.3, 111.8, 75.6, 39.4. Chiralpak OJ-H column
(250 Â 4.6 mm), 30% i-PrOH/hexane; 1.0 mL/min, 254 nm;
tmajor = 51.5 min, tminor = 36.0 min, ee = 87%.
4d: orange oil, 95% yield. 1H NMR (400 MHz, CDCl3) d 8.12 (d,
J = 8.0 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.78 (t, J = 8.0 Hz, 1H), 7.70
(t, J = 8.0 Hz, 1H), 6.99 (d, J = 8.0 Hz, 2H), 6.84 (d, J = 8.0 Hz, 1H),
5.43 (dd, J = 12.0, 8.0 Hz, 1H), 5.27–5.18 (m, 1H), 5.12 (dd,
J = 12.0, 8.0 Hz, 1H), 3.89 (s, 3H). 13C NMR (100 MHz, CDCl3) d
183.8, 181.2, 146.6, 145.3, 135.4, 133.3, 132.6, 129.2, 127.2,
126.3, 121.2, 121.0, 114.7, 111.0, 56.0, 39.5. Chiralpak OJ-H column
(250 Â 4.6 mm), 30% i-PrOH/hexane; 1.0 mL/min, 254 nm;
tmajor = 60.7 min, tminor = 21.9 min, ee = 88%.
4l: orange solid, 94% yield, mp 153–155 °C. 1H NMR (400 MHz,
CDCl3) d 8.12 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.82–7.77
(m, 1H), 7.74–7.69 (m, 1H), 7.59 (q, J = 8.0 Hz, 4H), 5.45–5.35 (m,
2H), 5.23 (td, J = 12.0, 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) d
183.5, 180.9, 153.4, 141.5, 135.6, 133.5, 132.5, 128.9, 128.7,
127.3, 126.5, 125.9, 125.9, 119.9, 75.8, 39.3. Chiralpak OJ-H column
(250 Â 4.6 mm), 30% i-PrOH/hexane; 0.8 mL/min, 254 nm;
tmajor = 22.1 min, tminor = 15.1 min, ee = 88%.
4e: orange solid, 97% yield, mp 56–58 °C. 1H NMR (400 MHz,
CDCl3) d 8.15–8.04 (m, 2H), 7.80–7.76 (m, 1H), 7.72–7.68 (m,
1H), 7.46–7.44 (m, 1H), 7.41–7.39 (m, 1H), 7.25–7.18 (m, 2H),
5.73 (dd, J = 12.0, 8.0 Hz, 1H), 5.41 (dd, J = 12.0, 8.0 Hz, 1H), 4.97
(dd, J = 12.0, 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) d 183.7,
181.0, 154.2, 135.5, 134.5, 134.0, 133.3, 132.7, 130.1, 129.5,
129.1, 129.0, 127.2, 127.2, 126.4, 119.4, 75.0, 37.1. Chiralpak AS-
4m: orange solid, 97% yield, mp 105–107 °C. 1H NMR (400 MHz,
CDCl3) d 8.13 (d, J = 8.0 Hz, 1H), 8.09–8.04 (d, J = 8.0 Hz, 1H), 7.81–
7.76 (m, 1H), 7.72–7.68 (m, 1H), 7.32 (s, 1H), 6.31–6.30 (m, 1H),
6.23 (m, 1H), 5.50–5.46 (m, 1H), 5.31–5.25 (m, 1H), 5.21–5.16
(m, 1H). 13C NMR (100 MHz, CDCl3) d 183.2, 181.0, 154.0, 149.8,
142.2, 135.5, 133.4, 132.5, 129.0, 127.2, 126.4, 118.0, 110.6,
107.4, 74.7, 33.4. Chiralpak AS-H column (250 Â 4.6 mm), 10%
H
column (250 Â 4.6 mm), 10% i-PrOH/hexane; 1.0 mL/min,
254 nm; tmajor = 37.3 min, tminor = 34.0 min, ee = 87%.
4f: orange oil, 96% yield. 1H NMR (400 MHz, CDCl3) d 8.20–8.03
(m, 2H), 7.79–7.75 (m, 1H), 7.72–7.68 (m, 1H), 7.66–7.55 (m, 1H),
7.43 (dd, J = 8.0, 4.0 Hz, 1H), 7.25 (dd, J = 8.0, 4.0 Hz, 1H), 7.19–7.09
(m, 1H), 5.70 (dd, J = 8.0, 4.0 Hz, 1H), 5.42 (dd, J = 12.0, 8.0 Hz, 1H),
4.92 (dd, J = 12.0, 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) d 183.8,
181.0, 154.2, 136.2, 135.5, 133.5, 133.3, 132.6, 129.6, 129.4,
129.0, 127.9, 127.2, 126.4, 124.5, 119.6, 74.9, 39.9. Chiralpak AS-
i-PrOH/hexane; 1.0 mL/min, 254 nm; tmajor = 40.1 min, tminor
=
50.0 min, ee = 88%.
4n: orange solid, 95% yield, mp 115À117 °C. 1H NMR (400 MHz,
CDCl3) d 8.14 (d, J = 8.0 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.81–7.77
(m, 1H), 7.72–7.68 (m, 1H), 7.20 (d, J = 4.0 Hz, 1H), 7.11 (d,
J = 4.0 Hz, 1H), 6.94–6.92 (m, 1H), 5.64–5.60 (m, 1H), 5.46–5.60
(m, 1H), 5.16–5.11 (m, 1H). 13C NMR (100 MHz, CDCl3) d 183.3,
H
column (250 Â 4.6 mm), 10% i-PrOH/hexane; 1.0 mL/min,
254 nm; tmajor = 33.4 min, tminor = 28.9 min, ee = 85%.

186
E. Zhou et al. / Tetrahedron: Asymmetry 25 (2014) 181–186
181.0, 153.1, 139.0, 135.5, 133.4, 132.5, 129.0, 127.2, 126.9, 126.6,
126.4, 125.4, 119.9, 76.8, 34.8. Chiralpak AS-H column
(250 Â 4.6 mm), 10% i-PrOH/hexane; 1.0 mL/min, 254 nm;
tmajor = 37.4 min, tminor = 34.0 min, ee = 88%.
131.6, 131.5, 128.8, 127.2, 127.0, 126.0, 125.6, 121.2, 55.3, 46.3,
29.7. Chiralpak AS-H column (250 Â 4.6 mm), 10% i-PrOH/hexane;
1.0 mL/min, 254 nm; tmajor =24.5 min, tminor = 28.1 min, ee = 91%.
4o: orange solid, 75% yield, mp 103–105 °C. 1H NMR (400 MHz,
CDCl3) d 8.13 (d, J = 8.0 Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.81–7.77
(m, 1H), 7.73–7.69 (m, 1H), 5.03–4.97 (m, 1H), 4.73–4.68 (m,
1H), 4.07–4.00 (m, 1H), 1.94–1.82 (m, 1H), 1.73–1.63 (m, 1H),
1.36–1.21 (m, 8H), 0.84 (s, 3H). 13C NMR (100 MHz, CDCl3) d
183.9, 180.9, 153.9, 135.3, 133.2, 132.7, 129.1, 127.1, 126.3,
121.0, 77.2, 34.7, 31.5, 30.3, 27.0, 22.4, 13.9. Chiralpak AD-H col-
umn (250 Â 4.6 mm), 10% i-PrOH/hexane; 0.8 mL/min, 254 nm;
tmajor = 17.4 min, tminor = 20.1 min, ee = 87%.
Acknowledgments
This work was supported by the NSFC (91017005), Key Project
of Ministry of Education (313040), the Scientific and Technological
innovative Research Team of Wuhan (2013070204020048), the Re-
search Fund for the Doctoral Program of Higher Education of China
(20100141110021), and the Fundamental Research Funds for the
Central Universities (2012306020202, 201130602020001).
4p: orange solid, 97% yield, mp 111–113 °C. 1H NMR (400 MHz,
CDCl3) d 8.13 (d, J = 8.0 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.81–7.76
(m, 1H), 7.70 (t, J = 8.0 Hz, 1H), 5.09 (dd, J = 12.0, 8.0 Hz, 1H), 4.79
(dd, J = 12.0, 8.0 Hz, 1H), 3.85–3.79 (m, 1H), 1.94–1.84 (m, 2H),
1.80–1.77 (m, 1H), 1.65–1.57 (m, 3H), 1.28–1.24 (m, 1H), 1.19–
1.09 (m, 3H), 1.08–0.96 (m, 1H). 13C NMR (100 MHz, CDCl3) d
184.0, 180.8, 154.1, 135.2, 133.2, 132.7, 129.2, 127.2, 126.3,
121.0, 75.9, 40.6, 38.4, 31.3, 31.2, 26.0, 26.0, 26.0. Chiralpak AS-H
column (250 Â 4.6 mm), 10% i-PrOH/hexane; 0.8 mL/min,
254 nm; tmajor = 23.7 min, tminor = 30.2 min, ee = 93%.
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