Asymmetric synthesis of 1,2,3-trisubstituted indanes via an enantioselective copper(II)-catalyzed asymmetric nitroaldol reaction followed by an intramolecular Michael cyclization

Article abstract of DOI:10.1016/j.tetasy.2013.05.005

Herein we describe a novel approach for the synthesis of a chiral 1,2,3-trisubstituted indane, a privileged substructure in medicinal chemistry, via an enantioselective nitroaldol reaction and subsequent intramolecular Michael addition. The asymmetric cop

Full text of DOI:10.1016/j.tetasy.2013.05.005

Tetrahedron: Asymmetry 24 (2013) 699–705
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Tetrahedron: Asymmetry
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Asymmetric synthesis of 1,2,3-trisubstituted indanes via
an enantioselective copper(II)-catalyzed asymmetric nitroaldol
reaction followed by an intramolecular Michael cyclization
⇑
Hongling Yuan, Junhao Hu, Yuefa Gong
School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan 430074, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 February 2013
Accepted 7 May 2013
Herein we describe a novel approach for the synthesis of a chiral 1,2,3-trisubstituted indane, a privileged
substructure in medicinal chemistry, via an enantioselective nitroaldol reaction and subsequent intramo-
lecular Michael addition. The asymmetric copper(II)-catalyzed reactions of ortho-formyl cinnamates,
ortho-formyl cinnamonitrile, or ortho-formyl a-benzalketones with nitromethane were carried out using
the C1-symmetric chiral secondary diamine L1 as a ligand, which afforded the nitroaldol products in high
yields (up to 92%) and with good to excellent enantioselectivities (up to 97%) under mild conditions. The
notable effect of the base and the dosage of nitromethane on the reaction are also discussed.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
stance classes, a variety of synthetic strategies to obtain this type
of compound have been developed. General synthetic methods in-
Indanes have found widespread application as key structural
units in medicinal chemistry;1 many natural and synthetic com-
pounds with this skeleton have shown significant biological activ-
ities.2 For example, secaloside A, which is isolated mainly from rye,
exhibits potent anti-tumor activity;3 SB-209670 and SB-217242
are highly potent antagonists of endothelin receptors;4 indatraline
[( )-trans-3-(3,4-dichlorophenyl)-N-methyl-1-indanamine] is an
uptake inhibitor with high affinity for dopamine, serotonin, and
norepinephrine transporters.5 Due to the importance of these sub-
clude the reduction of indanoes,6 [3+2]cycloaddition of a benzyl
cation with styrenes7 and palladium catalyzed intramolecular car-
boannulation reactions.8 These approaches often facilitate the dias-
teroselective synthesis of indanes, but there are only a few reports
on their enantioselective synthesis.9 Therefore, the development of
new strategies for the enantioselective synthesis of 1,2,3-trisubsti-
tuted indanes still remains an active field of research.
Recently, much effort has been devoted toward the develop-
ment of catalytic asymmetric nitroaldol reactions by metal cataly-
O
EWG
NO2
*
CHO
Path a
R
O
R
CH3NO2
+
R
EWG
EWG
NO2
1
OH
*
OH
NO2
Path b
R
R
NO2
EWG
EWG
Scheme 1. Possible reactions between 1 and nitromethane.
⇑
Corresponding author. Fax: +86 27 8754 3632.
E-mail address: gongyf@mail.hust.edu.cn (Y. Gong).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.05.005

700
H. Yuan et al. / Tetrahedron: Asymmetry 24 (2013) 699–705
Table 1
Ligand and copper salt screeninga
N
N
H
L5
N
H
L1
N
H
L3
N
H
L2
H2N
N
H
N
H
H
N
H
N
H
L4
Entry
Catalyst
DIPEA (equiv)
Timec (h)
Yieldd (%)
dre
eef (%)
1b
2b
3b
4
5
6
7
8
9
10
11
12
13
L1/Cu(OAc)2ꢀH2O
L1/Cu(OAc)2ꢀH2O
L1/Cu(OAc)2ꢀH2O
L1/Cu(OAc)2ꢀH2O
L2/Cu(OAc)2ꢀH2O
L3/Cu(OAc)2ꢀH2O
L4/Cu(OAc)2ꢀH2O
L5/Cu(OAc)2ꢀH2O
L1/CuCl2ꢀ2H2O
L1/CuCl
0.1
0.2
1.0
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
24
18
12
24
24
24
24
24
24
30
30
30
48
82 2a
90 3a
90 3a
82 3a
79 3a
76 3a
75 3a
77 3a
58 3a
70 3a
49 3a
66 3a
20 3a
—
87
79:21
76:24
79:21
76:24
73:27
74:26
69:31
75:25
70:30
73:27
71:29
72:28
82/71
65/43
87/73
ꢁ45/ndg
81/ndg
ꢁ68/ndg
69/ndg
81/ndg
59/85
80/53
57/37
86/11
L1/CuBr2
L1/CuCN
L1/CuSO4ꢀ5H2O
a
Unless otherwise stated, reactions were carried out with 1a (0.2 mmol), nitromethane (2.0 mmol, 10 equiv), ligand–Cu(II) complex (5 mol %), and DIPEA (107 lL,
0.1 equiv) for the indicated time in THF (1.0 mL) at 4 °C, then 3.0 mL of nitromethane was added and the solution was stirred continuously for another 12 h.
b
No additional 3.0 mL of nitromethane was added.
Time of nitroaldol reaction, except for entry 2.
c
d
Isolated yield.
e
Determined by 1H NMR spectroscopy of the crude products.
f
Enantiomeric excess was determined by HPLC analysis.
Not determined.
g
sis and organocatalysis.10 Our group has also developed a series of
novel chiral diamine ligands for copper-catalyzed asymmetric
nitroaldol reactions.10a Motivated by this work, we anticipated that
the two kinds of different anions generated during the asymmetric
nitroaldol reaction would undergo intramolecular Michael addi-
tion with various intramolecular electron-deficient alkenes 1 com-
petitively to yield either oxa-heterocyclic products (path a) or
carbocyclic products (path b) under the basic conditions
(Scheme 1). Luzzio et al. reported on a tandem nitroaldol/oxa-Mi-
chael route to the 1,3-disubstituted-1,3-dihydrobenzo[c] furan
system utilizing 1,1,3,3-tetramethylguanidine as the catalyst.11
However, to the best of our knowledge, the asymmetric nitroaldol
reaction followed by a carbocyclic reaction has not been reported.
Herein, we report a new synthetic approach to 1,2,3-trisubstituted
indanes via a highly enantioselective copper(II)-catalyzed asym-
metric nitroaldol reaction followed by an intramolecular Michael
cyclization.
0.1 equiv of diisopropylethylamine (DIPEA) in THF at 4 °C. The
product analysis showed the common nitroaldol product 2a was
produced predominantly rather than the expected ring-closure
products 3a, and its ee value was determined by chiral HPLC (Ta-
ble 1, entry 1). When an additional amount of DIPEA was added
into the reaction system, the nitroaldol product 2a disappeared
readily and was converted into the carbocyclic compound 3a with
three adjacent stereogenic centers. Thus, the stereochemistry of
the reaction was investigated by means of chiral HPLC and 1H
NMR. Two pairs of enantiomers were clearly detected, and the ee
value for the major isomer was apparently higher than that for
the minor isomer. In addition, the ee value of 3a generated under
the above conditions was lower than that of 2a, which indicates
that a racemization process happened through a competitive
reversible nitroaldol reaction during the intramolecular Michael
reaction (entries 2 and 3). At this juncture, we found a noteworthy
phenomenon that the addition of a large excess of nitromethane to
the reaction mixture, instead of additional DIPEA, also led to the
complete conversion of 2a into 3a. Moreover, in this case there
was no detectable loss in the enantiomeric purity for the major iso-
mer (entry 4). The major isomer can be isolated from the minor
isomer by silica gel column chromatography, and their structures
were identified as anti-3a and syn-3a by their spin splitting con-
stants and NOE analysis (Scheme 2).
2. Results and discussion
Our initial studies began with the copper(II)-catalyzed reaction
between (E)-ethyl 3-(2-formylphenyl)acrylate 1a and nitrometh-
ane. The reaction was first performed using 5 mol % of L1 and
5 mol % of Cu(OAc)2ꢀH2O as the catalyst system in the presence of
OH
OH
CH3NO2
+
OH
NO2
CH3NO2
OC2H5
NO2
L/Cu(OAc)2
NO2
CHO
DIPEA/THF,
4°C
OC2H5
+
O
O
O
OC2H5
OC2H5
O
3a
syn-
3a
anti-
2a
1a
major
minor
Scheme 2. L1–Cu(OAc)2 catalyzed nitroaldol reaction of 1a.

H. Yuan et al. / Tetrahedron: Asymmetry 24 (2013) 699–705
701
Table 2
camphor amine with
L
-alanine also showed inferior enantioselec-
Optimization of the reaction parametersa
tivities (entries 8). Among all of the ligands tested, L1 was identi-
fied to be the best choice in terms of both the yield and
enantioselectivity of the product 3a. The effect of some representa-
tive copper salts on the reaction was also assessed in combination
with L1 in nitromethane at 4 °C (entries 9–13). Evidently, copper
acetate provided the most satisfactory results among the copper
salts tested, and was used in the following experiments.
Entry
Solvent
Base
Timeb (h)
Yieldc (%)
drd
eee (%)
1
2
3
4
5
6
7
8
THF
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
Et3N
24
6
82 3a
82 3a
51 3a
62 3a
43 3a
56 3a
82 3a
81 3a
51 3a
80 2a
nd
79:21
79:21
78:22
74:26
81:19
75:25
76:24
74:26
76:24
—
87/73
35/72
31/1
39/53
59/26
13/10
81/76
70/59
16/9
—
CH3NO2
MeCN
CH2Cl2
Toluene
CH3OH
Et2O
24
24
36
36
24
24
30
36
48
48
36
The reaction conditions were then optimized utilizing this cata-
lyst system. Further optimization was carried out by screening sol-
vents, bases and reaction temperature. The observed data are
given in Table 2. When the reaction was carried out in nitromethane,
it proceeded smoothly and furnished indane 3a in high yield, but
with rather low enantioselectivity (Table 2, entry 2). Ether solvents
provided better results than other types of solvents such as nitro-
methane, acetonitrile, dichloromethane, toluene, and methanol;
among them THF proved to be the best solvent (Table 2, entries 1–7).
Next, various organic bases were assessed. Preliminary results
showed that the use of DIPEA gave the highest yield and enantiose-
lectivity of 3a (Table 2, entries 1, 8, and 9). Meanwhile, N-methyl-
morpholine (NMM) favored the formation of nitroaldol product 2a
(entry 10), while imidazole and DMAP as the base showed worse
catalytic activity, and almost no 2a and 3a could be isolated in each
case (Table 2, entries 11 and 12). We also found that the reaction
temperature had a certain influence on the reaction. At ꢁ20 °C,
the reaction time was prolonged, but the ee value was elevated
to 91% (entry 13). Thus, the optimal results (91% yield, 91% ee)
were achieved when the reaction of 1a with nitromethane
(10 equiv) and DIPEA (0.1 equiv) was performed in THF at ꢁ20 °C
in the presence of L1–Cu(OAc)2ꢀH2O as the catalyst.
THF
9
THF
THF
Piperidine
NMM
10
11
12
13f
THF
THF
THF
Imidazole
DMAP
DIPEA
—
—
83:17
—
—
91/77
nd
91 3a
a
Unless otherwise stated, reactions were carried out with 1a (0.2 mmol), nitro-
methane (2 mmol, 10 equiv), L1–Cu(OAc)2ꢀH2O complex (5 mol %), and base
(0.1 equiv) in the indicated solvent (1.0 mL) at 4 °C, then 3.0 mL of nitromethane
was added and the solution was stirred continuously for 6–12 h.
b
Time for the nitroaldol reaction, except for entry 2.
c
Isolated yield.
d
Determined by 1H NMR spectroscopy of the crude products.
e
Enantiomeric excess was determined by HPLC analysis.
Reaction was performed at ꢁ20 °C.
f
Based on the above observations, we realized that the combina-
tion of an enantioselective nitroaldol reaction and subsequent Mi-
chael addition promoted by an excess amount of nitromethane was
an ideal choice for the synthesis of chiral 1,2,3-trisubstituted
indanes.
The catalytic activity of other chiral diamine ligands L2–L5 was
also estimated under the above reaction conditions. When ligand
L2 derived from
versed enantiomer was formed with much lower enantioselectivity
(entry 5). The ligands L3 and L4 derived from (+)-(1S,2S,5R)-men-
thylamine showed a similar change in stereoselectivity but failed
to offer better results (entries 6 and 7). Ligand L5 prepared from
Under the optimized conditions, the substrate scope and limita-
tions of this process were then investigated. For this purpose, var-
ious intramolecular Michael acceptors such as enones, cinnamates,
cinnamonitrile, and a nitroolefin were prepared and utilized. The
observed results are listed in Table 3, and the total reaction times
varied from 42 to 80 h. Cinnamates 1a–f were ideal substrates, and
D-proline was employed, the configuration-in-
Table 3
Copper(II)-catalyzed asymmetric synthesis of 1,2,3-trisubstituted indanesa
OH
OH
5 mol% L1
/Cu(OAc)2·H2O
NO2
CHO
CH3NO2
+ CH3NO2
EWG
NO2
R
R
R
DIPEA (0.1equiv),
THF, -20 °C
EWG
EWG
1e
1h
: R=4-NO2, EWG=COOC2H5
: R=H, EWG=4-CH3OC6H4CO
: R=H, EWG=4-ClC6H4CO
: R=H, EWG=CN
1a: R=H, EWG=COOC2H5
1b: R=H, EWG=COOCH3
1c: R=H, EWG=COOC4H9-n
1d: R=H, EWG=COOC4H9-t
1f
1i
1j
: R=3,4-OCH2O, EWG=COOC2H5
1g
: R=H, EWG=PhCO
Entry
Substrate
Timeb (h)
Yield 3c (%)
drd
eee (%)
1
2
3
4
5
6
7
8
9
10
1a
1b
1c
1d
1e
1f
1g
1h
1i
36, 12
33, 12
40, 12
40, 10
35, 9
40,12
52, 8
58, 8
91
92
89
90
85
89
50
56
40
82
83:17
86:14
82:18
87:13
80:20
86:14
78:22
76:24
69:31
86:14
91/77
93/73
85/56
97/69
96/76
97/71
58/ndf
81/nd
0/nd
70, 10
36, 12
1j
92/nd
a
Reactions were carried out with 1 (0.2 mmol), nitromethane (2 mmol, 10 equiv), L1–Cu(OAc)2ꢀH2O complex (5 mol %), and DIPEA (107
lL, 0.1 equiv) in THF (1.0 mL) at
ꢁ20 °C, and then 3.0 mL of nitromethane was added to the solution.
b
Reaction time for each of the two steps.
c
Isolated yield.
d
Determined by 1H NMR spectroscopy of the crude products.
e
Enantiomeric excess of the diastereomers was determined by HPLC analysis.
Not determined.
f

702
H. Yuan et al. / Tetrahedron: Asymmetry 24 (2013) 699–705
Path A
OH
OH
CHO
CH3NO2
NO2
1) Zn/HCl
2) NaOH
NH
L1-Cu(OAc)2
COOC2H5
COOC2H5
COOC2H5
2a
6a
Path B
OH
Br
OH
NH·HCl
O
NO2
NH2
1) Zn/HCl
2) NaOH
O
N
CH2Cl2, 0 °C-rt
Br
O
Br
7
(S)-
OH
COOC2H5
Pd(OAc)2, PPh3, Et3N
N
1) HCl/EtOH
2) NaOH
NH
COOC2H5
COOC2H5
6a
Scheme 3. Determination of the absolute configuration of 2a.
their reactions proceeded readily under the optimal conditions to
give the corresponding 1,2,3-trisubstituted indanes 3a–f with high
yields (up to 92%) and with good to excellent enantioselectivities
(up to 97% ee), respectively (Table 3, entries 1–6). It was clear that
the structure of the ester moiety had an effect on the reaction
enantioselectivity (Table 3, entries 3 and 4) with cinnamate 1d,
with a bulky t-butyl group giving a higher ee value than substrate
1c with an n-butyl group.
the enone 1g with nitromethane did not take place in the absence
of either DIPEA or L1–Cu(OAc)2ꢀH2O complex. These results clearly
indicate that the combination catalysis of a base and a diamine li-
gand–Cu salt complex is necessary for this transformation. In addi-
tion, the employment of nitroolefin 1k as an intramolecular
Michael acceptor did not give the desired product 3k under the
same conditions, possibly due to its ease for oligomerization under
basic conditions.
OH
5mmol %L1/Cu(OAc)2·H2O
DIPEA (0.1equiv),THF, -20 °C
CHO
NO2
+ CH3NO2
NO2
NO2
none
The electronic properties of the substituents on the aromatic
ring were also found to have an effect on the reaction rate. The
reaction of 1e with an electron-withdrawing substituent, such as
an –NO2 group, was much faster than that of 1f with an elec-
tron-donating substituent such as an –OCH2O– group (entries 5
and 6). Nonetheless, both of them gave excellent ee values despite
a slight decrease in the product yield. We next turned our attention
to another typical Michael acceptor enone. Relatively lower yields
and ee values were observed in the case of the enones 1g–1i (en-
tries 7–9), which indicated that carbonyl group had a negative ef-
fect on the nitroaldol reaction, maybe due to its competitive
coordinating role to the copper(II) ion. In addition, the electronic
properties of the substituents on the aromatic ring of enones had
an enormous influence on the reaction enantioselectivity. The reac-
tion of enone 1h with an electron-donating methoxy group on the
benzene ring afforded good yield and ee values, whereas that of 1i
with an electron-withdrawing chloro group proceeded sluggishly,
giving the desired product in only 40% yield with almost no enanti-
oselectivity (entries 8 and 9). Next, cinnamonitrile was investi-
gated as an intramolecular Michael acceptor. As expected, the
behavior of cinnamonitrile was similar to the cinnamates, and
product 3j was obtained with high yield and excellent enantiose-
lectivity (Table 3, entry10). It is noteworthy that the reaction of
We also decided to determine the absolute configuration of
anti-3a. Some derivatives of anti-3a such as 4a and 5a, were thus
prepared for single crystal X-ray diffraction. However, we were un-
able to obtain single crystals for each of the derivatives.
OH
OH
O
Br
NH
NH2
O
O
OC2H5
OC2H5
4a
5a
As a result, we tried to determine the absolute configuration of
the intermediate 2a through derivation from the known chiral
source (S)-7 along the routes shown in Scheme 3. As a conse-
quence, 2a was assigned to have an (S)-configuration. This result
is consistent with our previous reports.12

H. Yuan et al. / Tetrahedron: Asymmetry 24 (2013) 699–705
703
AD-H, hexane/i-PrOH = 90:10, flow rate: 0.5 mL/min, k = 210 nm),
tmajor = 38.8 min, tminor = 44.7 min, 91% ee. syn-3a: 1H NMR
(400 MHz, CDCl3) d 7.49–7.42 (m, 1H), 7.42–7.34 (m, 2H), 7.27–
7.17 (m, 1H), 5.58 (d, J = 6.3 Hz, 1H), 5.36 (t, J = 6.6 Hz, 1H), 4.19–
4.08 (m, 3H), 3.34 (s, 1H), d 2.95 (dd, J = 16.0, 5.3 Hz, 3H), 2.79
(dd, J = 16.0, 7.5 Hz, 1H),1.22 (t, 3H).
3. Conclusion
In conclusion, we have developed a novel synthetic method for
1,2,3-trisubstituted indanes via the copper(II)-catalyzed asymmet-
ric nitroaldol reaction of ortho-formyl cinnamates, ortho-formyl
cinnamonitriles, and ortho-formyl
a-benzalketones with subse-
quent intramolecular Michael addition under mild conditions.
The reaction provided a wide variety of 1,2,3-trisubstituted ind-
anes in good yields (up to 92%) with good to excellent enantiose-
lectivities (up to 97%). Further applications of this methodology
are currently underway in our laboratory.
4.3.2. (1R,2S,3S)-Methyl (3-hydroxy-2-nitroindan-1-yl)acetate
anti-3b
Pale yellow oil. ½a D25
ꢂ
¼ ꢁ23:2 (c 2.4, CHCl3); 1H NMR (400 MHz,
CDCl3) d 7.47–7.42 (m, 1H), 7.41–7.36 (m, 2H), 7.21–7.17 (m, 1H),
5.69 (d, J = 5.6 Hz, 1H), 5.07 (dd, J = 7.3, 5.6 Hz, 1H), 4.11 (dd,
J = 12.8, 6.5 Hz, 1H), 3.70 (s, 3H), 3.42 (s, 1H), 3.04 (dd, J = 16.7,
5.4 Hz, 1H), 2.93 (dd, J = 16.7, 6.8 Hz, 1H). 13C NMR (100 MHz,
CDCl3) d 171.66, 139.57, 139.14, 129.80, 128.77, 97.68, 78.88,
77.36, 52.09, 43.17, 37.10. HRMS-ESI (m/z) calcd for C12H13NO5
[M+Na+]: 274.0691, found: 274.0687. HPLC (Chiralpak AD-H, hex-
ane/i-PrOH = 90:10, flow rate: 0.5 mL/min, k = 210 nm), tma-
jor = 42.9 min, tminor = 49.6 min, 93% ee. syn-3b: 1H NMR
(400 MHz, CDCl3) d 7.61–7.55 (m, 1H), 7.54–7.49 (m, 1H), 7.27–
7.21 (m, 2H), 5.87 (d, J = 5.9 Hz, 1H), 5.23 (dd, J = 7.9, 5.9 Hz, 1H),
4.30 (dd, J = 15.3, 7.9 Hz, 1H), 3.71 (s, 2H), 3.51 (s, 1H), d 3.46
(dd, J = 31.4, 6.5 Hz, 1H), 3.11 (dd, J = 33.0, 6.0 Hz, 1H).
4. Experimental
4.1. General
Solvents were purified according to standard procedures and
distilled before use. Reagents and starting materials purchased
from commercial suppliers were used without further purification
unless otherwise stated. For thin-layer chromatography (TLC), sil-
ica gel plates GF 254 were used, and compounds were visualized
by irradiation with UV light, I2, or by treatment with basic KMnO4.
Optical rotations were measured in the solvent indicated. Flash
chromatography was carried out on silica gel 200–300 mesh.
NMR spectra were measured on a 400 MHz spectrometer. 1H
NMR chemical shifts are reported in ppm with tetramethylsilane
(TMS, d 0 ppm) as the internal standard. Data for 1H NMR are re-
ported as follows: chemical shift (ppm), and multiplicity (s = sin-
glet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad).
Data for 13C NMR are reported in ppm. High resolution mass spec-
troscopy analyses (HRMS) were measured using ESI ionization.
High performance liquid chromatography (HPLC) analysis was per-
formed on chiral columns.
4.3.3. (1R,2S,3S)-n-Butyl (3-hydroxy-2-nitroindan-1-yl)acetate
anti-3c
Colorless oil. ½a D25
ꢂ
¼ ꢁ23:4 (c 2.5, CHCl3); 1H NMR (400 MHz,
CDCl3) d 7.48–7.43 (m, 1H), 7.41–7.36 (m, 2H), 7.23–7.17 (m,
1H), 5.70 (d, J = 5.5 Hz, 1H), 5.10 (dd, J = 7.1, 5.5 Hz, 1H), 4.14–
4.06 (m, 3H), 3.27 (s, 1H), 3.03 (dd, J = 16.6, 5.4 Hz, 1H), 2.93 (dd,
J = 16.6, 6.6 Hz, 1H), 1.59 (dt, J = 14.6, 6.8 Hz, 2H), 1.35 (dd,
J = 15.1, 7.5 Hz, 2H), 0.93 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz,
CDCl3) d 171.23, 139.68, 139.28, 129.74, 128.71, 124.52, 123.32,
97.63, 78.91, 65.07, 43.28, 37.34, 30.45, 19.04, 13.63. HRMS-ESI
(m/z) calcd for C15H19NO5 [M+Na+]: 316.1161, found: 316.1155.
HPLC (Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate: 0.5 mL/
min, k = 210 nm), tmajor = 50.2 min, tminor = 64.6 min, 85% ee. syn-
3c: 1H NMR (400 MHz, CDCl3) d 7.50–7.46 (m, 1H), 7.31–7.28 (m,
1H), 7.24–7.20 (m, 1H), 5.82 (dd, J = 9.7, 2.9 Hz), 4.68 (dd,
J = 13.3, 9.7 Hz), 4.14–4.06 (m, 3H), 3.27 (s, 1H), 3.10 (dd, J = 14.7,
7.4 Hz), 3.03 (dd, J = 10.6, 5.3 Hz), 1.62–1.51 (m, 2H), 1.30 (ddd,
J = 21.4, 14.6, 7.3 Hz, 2H), 0.96–0.86 (m, 3H).
4.2. General procedure for the enantioselective synthesis of
1,2,3-trisubstituted indanes
Ligand L1 (0.01 mmol, 5 mol %) and Cu(OAc)2ꢀH2O (2 mg,
0.01 mmol, 5 mol %) were added to a test tube containing absolute
THF (1.0 mL), and the mixture was stirred for 1 h at room temper-
ature to afford a blue solution. To the mixture the corresponding
aldehyde 1a (41 mg, 0.2 mmol) was added, and the solution was
then cooled to ꢁ20 °C with stirring, which was followed by the
4.3.4. (1R,2S,3S)-t-Butyl (3-hydroxy-2-nitroindan-1-yl)acetate
anti-3d
addition of nitromethane (107
lL, 5 mmol, 10 equiv) and DIPEA
Colorless oil. ½a D25
ꢂ
¼ ꢁ7:4 (c 2.2, CHCl3); 1H NMR (400 MHz,
(3.3 L, 0.1 equiv). Stirring was continued until all of the aldehyde
l
was fully consumed as indicated by TLC, and then 3.0 mL of nitro-
methane was added to the solution. The mixture was continuously
stirred at ꢁ20 °C and monitored by TLC until 2a was completely
CDCl3) d 7.47–7.41 (m, 1H), 7.41–7.35 (m, 2H), 7.24–7.18 (m,
1H), 5.69 (s, 1H), 5.11 (dd, J = 7.1, 5.6 Hz, 1H), 4.08 (dd, J = 12.4,
6.4 Hz, 1H), 3.42 (s, 1H), 2.94 (dd, J = 16.4, 5.2 Hz, 1H), 2.84 (dd,
J = 16.4, 6.6 Hz, 1H), 1.39 (s, 9H). 13C NMR (100 MHz, CDCl3) d
170.41, 139.71, 139.41, 129.64, 128.61, 124.46, 123.46, 97.70,
82.00, 78.94, 43.47, 38.58, 27.89. HRMS-ESI (m/z) calcd for
converted, then 7 lL of 3 M aqueous HCl was added. The solvent
was removed under reduced pressure, and the residue was directly
purified by column chromatography on silica gel, eluting with
petroleum ether and ethyl acetate to afford the product 3a–j.
C
15H19NO5 [M+Na+]: 316.1155, found: 316.1162. HPLC (Chiralpak
AD-H, hexane/i-PrOH = 85:15, flow rate: 0.5 mL/min, k = 210 nm),
tmajor = 18.0 min, tminor = 20.0 min, 97% ee. syn-3d: 1H NMR
(400 MHz, CDCl3) d 7.65–7.61 (m, 1H), 7.59–7.55 (m, 2H), 7.56–
7.51 (m, 1H), d 5.87 (s, 1H), 5.21 (dd, J = 13.0, 7.2 Hz, 1H), 4.28
(dd, J = 14.9, 7.3 Hz, 1H) 3.41 (s, 1H), 3.10 (dd, J = 11.0, 5.4 Hz,
1H), 3.04 (dd, J = 14.7, 6.2 Hz, 1H), 1.35 (s, 9H).
4.3. Spectroscopic data for the products
4.3.1. (1R,2S,3S)-Ethyl (3-hydroxy-2-nitroindan-1-yl)acetate
anti-3a
Colorless oil. ½a D25
ꢂ
¼ ꢁ19:1 (c 2.4, CHCl3); 1H NMR (400 MHz,
CDCl3) d 7.49–7.43 (m, 1H), 7.42–7.37 (m, 2H), 7.24–7.18 (m,
1H), 5.70 (d, J = 5.5 Hz, 1H), 5.10 (dd, J = 7.1, 5.6 Hz, 1H), 4.19–
4.09 (m, 3H), 3.32 (s, 1H), 3.03 (dd, J = 16.6, 5.3 Hz, 1H), 2.92 (dd,
J = 16.6, 6.7 Hz, 1H), 1.24 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz,
CDCl3) d 171.16, 139.63, 139.26, 129.77, 128.74, 124.52, 123.34,
97.70, 78.96, 61.21, 43.25, 37.42, 14.04. HRMS-ESI (m/z) calcd for
4.3.5. (1R,2S,3S)-Ethyl (3-hydroxy-2,5-dinitroindan-1-yl)acetate
anti-3e
White solid. Mp 92.5–94.2 °C. ½a D25
ꢂ
¼ ꢁ9:9 (c 3.3, CHCl3); 1H
NMR (400 MHz, CDCl3) d 8.31 (s, 1H), 8.25 (dd, J = 8.4, 2.1 Hz,
1H), 7.37 (d, J = 8.4 Hz, 1H), 5.74 (d, J = 5.4 Hz, 1H), 5.20 (dd,
J = 7.1, 5.5 Hz, 1H), 4.14 (dd, J = 7.1, 2.9 Hz, 3H), 3.59 (s, 1H), 3.04
C
13H15NO5 [M+Na+]: 288.0848, found: 288.0851. HPLC (Chiralpak

704
H. Yuan et al. / Tetrahedron: Asymmetry 24 (2013) 699–705
(dd, J = 5.6, 3.7 Hz, 2H), 1.24 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz,
CDCl3) d 170.68, 148.71, 146.32, 141.70, 125.20, 124.27, 120.38,
96.90, 77.80, 61.55, 43.14, 36.63, 14.02. HRMS-ESI (m/z) calcd for
(100 MHz, CDCl3) d 196.33, 140.36, 140.08, 139.65, 134.60,
129.85, 129.55, 129.18, 128.66, 124.55, 123.48, 97.88, 78.95,
42.67, 42.10. HRMS-ESI (m/z) calcd for C17H14ClNO4 [M+Na+]:
354.0509, found: 354.0498. HPLC (Chiralpak OD-H, hexane/i-
PrOH = 85:15, flow rate: 0.5 mL/min, k = 210 nm), tmajor = 36.2 min,
tminor = 53.0 min, 0% ee.
C
13H14N2O7 [M+Na+]: 333.0699, found: 333.0690. HPLC (Chiralpak
AD-H, hexane/i-PrOH = 80:20, flow rate: 0.5 mL/min, k = 210 nm),
tmajor = 19.5 min, tminor = 21.0 min, 96% ee. syn-3e: 1H NMR
(400 MHz, CDCl3) d 8.33 (dt, J = 8.4, 1.7 Hz, 1H), 8.26 (s, 1H), 7.50
(dd, J = 18.1, 8.4 Hz, 1H), 5.88 (ddd, J = 8.9, 5.9, 3.0 Hz, 1H), 5.62–
5.49 (m, 1H), 4.10–3.86 (m, 3H), 3.57 (s, 1H), 3.01–2.78 (m, 2H),
1.31 (t, J = 7.2 Hz, 3H).
4.3.10. (1R,2S,3S)-(3-Hydroxy-2-nitroindan-1-yl)acetonitrile
anti-3j
Pale yellow solid. Mp 94.0–95.1 °C.
½
a 2D5
ꢂ
¼ þ35:54 (c 1.8,
CHCl3); 1H NMR (400 MHz, CDCl3) d 7.55–7.46 (m, 3H), 7.40 (dd,
J = 8.0, 4.7 Hz, 1H), 5.77 (d, J = 6.3 Hz, 1H), 4.90 (dd, J = 8.2,
6.4 Hz, 1H), 4.08–3.95 (m, 1H), 3.23–3.00 (m, 3H). 13C NMR
4.3.6. (1R,2S,3S)-Ethyl (7-hydroxy-6-nitro-6,7-dihydro-5H-ind-
eno[5,6-d][1,3]dioxol-5-yl) acetate anti-3f
Pale yellow solid. Mp 93.6–94.0 °C. ½a D25
ꢂ
¼ ꢁ69:7 (c 1.2, CHCl3);
(100 MHz, CDCl3) d 139.22, 136.15, 130.22, 129.69, 124.68,
1H NMR (400 MHz, CDCl3) d 6.86 (s, 1H), 6.63 (s, 1H), 6.00 (d,
J = 1.0 Hz, 2H), 5.55 (d, J = 4.2 Hz, 1H), 5.06 (dd, J = 6.4, 4.9 Hz,
1H), 4.18–4.11 (m, 2H), 3.99 (q, J = 6.1 Hz, 1H), 3.28 (s, 1H), 2.95
(dd, J = 16.6, 5.4 Hz, 1H), 2.86 (dd, J = 16.6, 6.6 Hz, 1H), 1.26 (t,
J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) d 171.13, 149.43,
148.49, 132.91, 132.79, 104.65, 103.54, 101.65, 97.72, 78.68,
61.19, 43.12, 37.70, 14.03. HRMS-ESI (m/z) calcd for C14H15NO7
[M+Na+]: 332.0746, found: 332.0749. HPLC (Chiralpak AD-H, hex-
ane/i-PrOH = 90:10, flow rate: 0.5 mL/min, k = 210 nm), tma-
jor = 62.9 min, tminor = 72.7 min, 97% ee. syn-3f: 1H NMR
(400 MHz, CDCl3) d 7.13 (s, 1H), 7.04 (s, 1H), 6.05 (dd, J = 5.3,
1.3 Hz, 2H), 5.84 (dd, J = 9.5, 2.7 Hz, 1H), 4.51 (dd, J = 13.6, 9.6 Hz,
1H), 4.33–4.25 (m, 2H), d 4.19–4.10 (m, 1H), 3.19 (s, 1H), d 2.95
(dd, J = 16.7, 5.3 Hz, 1H), 2.86 (dd, J = 16.7, 6.6 Hz, 1H), 1.36 (t,
J = 7.1 Hz, 3H).
123.21, 116.66, 95.84, 77.38, 42.34, 20.88. HRMS-ESI (m/z) calcd
for C11H10N2O3 [M+Na+]: 241.0589, found: 241.0579. HPLC (Chir-
alpak AD-H, hexane/i-PrOH = 85:15, flow rate: 0.5 mL/min,
k = 210 nm), tmajor = 23.8 min, tminor = 30.0 min, 92% ee.
4.3.11. Procedure for the synthesis of the compound 6a
4.3.11.1. Path A: preparation of (E)-ethyl 3-(2-(1-hydroxy-2-
nitroethyl)phenyl)acrylate
2a.
Ligand
L1
(4.8 mg,
0.02 mmol, 5 mol %) and Cu(OAc)2ꢀH2O (4 mg, 0.02 mmol,
5 mol %) were added to a test tube containing absolute THF
(2.0 mL), and the mixture was stirred for 1 h at room temperature
to afford a blue solution. To the mixture the corresponding alde-
hyde 1a (82 mg, 0.4 mmol) was added with stirring, then the solu-
tion was cooled to ꢁ20 °C, after which nitromethane (214
4 mmol, 10 equiv) and DIPEA (3.3 L, 0.1 equiv) were added. The
stirring was continued until the aldehyde was fully consumed as
indicated by TLC, then 14 L of 3 M HCl aqueous was added, and
lL,
l
4.3.7. (1R,2S,3S)-2-(3-Hydroxy-2-nitroindan-1-yl)-1-
phenylethanone anti-3g
l
the mixture was concentrated and directly purified by column
chromatography on silica gel, eluting with petroleum ether and
ethyl acetate to afford product 2a (96 mg, 91%). 1H NMR
(400 MHz, CDCl3) d 8.04 (d, J = 15.7 Hz, 1H), 7.62 (d, J = 7.2 Hz,
1H), 7.55 (d, J = 7.7 Hz, 1H), 7.45 (td, J = 7.6, 1.1 Hz, 1H), 7.37 (dt,
J = 7.5, 3.8 Hz, 1H), 6.35 (d, J = 15.7 Hz, 1H), 5.85 (dd, J = 9.6,
2.9 Hz, 1H), 4.56 (dd, J = 13.3, 9.6 Hz, 1H), 4.46 (dd, J = 13.3,
3.0 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H). 13C
NMR (101 MHz, CDCl3) d 166.79, 140.36, 137.25, 132.24, 130.55,
128.99, 127.26, 126.64, 121.77, 80.59, 67.61, 61.02, 14.20.
Pale yellow solid. Mp 98.6–99.1 °C. ½a D25
¼ þ8:4 (c 1.2, CHCl3);
ꢂ
1H NMR (400 MHz, CDCl3) d 8.05–7.97 (m, 2H), 7.68–7.61 (m,
1H), 7.51 (dd, J = 15.5, 8.0 Hz, 3H), 7.37 (td, J = 13.1, 7.4 Hz, 2H),
7.16 (d, J = 7.3 Hz, 1H), 5.79 (d, J = 5.2 Hz, 1H), 5.06 (dd, J = 7.0,
5.3 Hz, 1H), 4.36 (dd, J = 12.5, 6.1 Hz, 1H), 3.70 (d, J = 5.8 Hz, 1H),
3.20 (s, 1H). 13C NMR (100 MHz, CDCl3) d 197.48, 140.32, 139.73,
136.27, 133.77, 129.80, 128.81, 128.56, 128.13, 124.51, 123.53,
97.94, 79.04, 42.81, 42.10. HRMS-ESI (m/z) calcd for C17H15NO4
[M+Na+]: 320.0899, found: 320.0897. HPLC (Chiralpak AS-H,
hexane/i-PrOH = 90:10, flow rate: 0.5 mL/min, k = 210 nm),
tmajor = 68.5 min, tminor = 86.4 min, 58% ee.
Preparation of ethyl 2-((4S)-1,2,3,4-tetrahydro-4-hydroxyiso-
quinolin-1-yl)acetate 6a. At first, Zn powder (390 mg, 6 mmol)
was added to a solution of 2a (0.3 mmol) in ethanol/H2O (10:3,
v/v) with rigorous stirring, and then concentrated HCl (2 mL) was
added. The mixture was stirred at room temperature for 4 h. The
solution was then neutralized by dilute aqueous NaOH until
pH = 10, and extracted with ethyl acetate. The organic phase was
dried over anhydrous Na2SO4, and evaporated under reduced pres-
sure. The crude product was purified by column chromatography
eluting with dichloromethane and methanol to afford the product
4.3.8. (1R,2S,3S)-2-(3-Hydroxy-2-nitroindan-1-yl)-1-(4-meth-
oxyphenyl)ethanone anti-3h
Pale yellow solid. Mp 99.5–101.0 °C. ½a D25
¼ þ5:5 (c 2.1, CHCl3);
ꢂ
1H NMR (400 MHz, CDCl3) d 7.95 (d, J = 8.9 Hz, 1H), 7.46 (d,
J = 7.0 Hz, 1H), 7.38–7.30 (m, 1H), 7.14 (d, J = 7.1 Hz, 1H), 6.95 (d,
J = 8.9 Hz, 1H), 5.75 (d, J = 4.3 Hz, 1H), 5.05 (dd, J = 6.8, 5.2 Hz,
1H), 4.31 (q, J = 6.1 Hz, 1H), 3.88 (s, 3H), 3.62 (d, J = 5.8 Hz, 2H),
3.29 (s, 1H). 13C NMR (100 MHz, CDCl3) d 195.91, 164.00, 140.55,
139.83, 130.46, 129.75, 129.39, 128.48, 124.51, 123.53, 113.94,
98.02, 79.16, 77.33, 77.22, 77.01, 55.56, 53.43, 43.05, 41.65.
HRMS-ESI (m/z) calcd for C18H17NO5 [M+Na+]: 350.1004, found:
350.1010. HPLC (Chiralpak AD-H, hexane/i-PrOH = 85:15, flow
rate: 0.5 mL/min, k = 210 nm), tmajor = 20.4 min, tminor = 24.5 min,
81% ee.
6a as a pale yellow solid (46 mg, 65% yield). ½a D25
¼ þ73:3 (c 2.0,
ꢂ
CH2Cl2). 1H NMR (400 MHz, CDCl3) d 7.41 (ddd, J = 8.9, 6.5,
2.9 Hz, 1H), 7.34–7.27 (m, 2H), 7.18–7.06 (m, 1H), 4.56 (dt,
J = 4.8, 2.9 Hz, 1H), 4.43 (ddd, J = 11.8, 9.7, 3.0 Hz, 1H), 4.26–4.14
(m, 2H), 3.28 (td, J = 12.5, 3.0 Hz, 1H), 3.12–2.99 (m, 2H), 2.84–
2.55 (m, 3H), 1.29 (dt, J = 13.3, 7.1 Hz, 3H). 13C NMR (101 MHz,
CDCl3) d 172.34, 172.11, 137.50, 137.21, 130.03, 129.40, 128.17,
127.95, 127.18, 127.00, 126.32, 125.14, 66.36, 66.02, 60.78, 60.71,
52.86, 52.12, 49.53, 46.11, 40.95, 39.91, 14.24, 14.18. HRMS-ESI
(m/z) calcd for C13H17NO3 [M+Na+]: 258.1106, found: 258.1109.
4.3.9. (1R,2S,3S)-1-(4-Chlorophenyl)-2-(3-hydroxy-2-nitroindan-
1-yl)ethanone anti-3i
Pale yellow solid. Mp 105.2–106.2 °C. ½a D25
¼ þ0:40 (c 1.4,
ꢂ
CHCl3); 1H NMR (400 MHz, CDCl3) d 7.96–7.92 (m, 2H), 7.51–7.47
(m, 3H), 7.37 (dd, J = 7.3, 5.6 Hz, 2H), 7.15 (d, J = 7.3 Hz, 1H), 5.78
(d, J = 5.3 Hz, 1H), 5.03 (dd, J = 7.1, 5.4 Hz, 1H), 4.35 (dd, J = 13.0,
6.4 Hz, 1H), 3.66 (d, J = 5.9 Hz, 2H), 3.25 (S, 1H). 13C NMR
4.3.11.2.
7.
Path
B:
(S)-1-(2-Bromophenyl)-2-nitroethanol
Ligand L1 (12 mg, 0.05 mmol, 5 mol %) and Cu(OAc)2ꢀH2O
(10 mg, 0.05 mmol, 5 mol %) were added to a test tube containing
absolute THF (5 mL), and the mixture was stirred for 1 h at room

H. Yuan et al. / Tetrahedron: Asymmetry 24 (2013) 699–705
705
temperature to afford a blue solution. To the mixture the corre-
sponding aldehyde 1 (185 mg, 1 mmol) was added with stirring,
and the solution was then cooled to –20 °C, after which nitrometh-
ized with 1 M NaOH aqueous until pH = 10 and extracted with
ethyl acetate. The organic phase was dried over anhydrous Na2SO4
and evaporated under reduced pressure. The crude product was
purified by column chromatography eluting with dichloromethane
and methanol to afford product 6a as a pale yellow solid (40 mg,
ane (535
lL, 10 mmol, 10 equiv) and DIPEA (165
lL, 1.0 equiv)
were added. After 350
lL of 3 M aqueous HCl was added, the mix-
ture was concentrated and directly purified by column chromatog-
raphy on silica gel, eluting with petroleum ether and ethyl acetate
70%). ½a 2D5
ꢂ
¼ þ99:2 (c 2.1, CH2Cl2). 1H NMR (400 MHz, CDCl3) d
7.41 (ddd, J = 8.9, 6.5, 2.9 Hz, 1H), 7.34–7.27 (m, 2H), 7.18–7.06
(m, 1H), 4.56 (dt, J = 4.8, 2.9 Hz, 1H), 4.43 (ddd, J = 11.8, 9.7,
3.0 Hz, 1H), 4.26–4.14 (m, 2H), 3.28 (td, J = 12.5, 3.0 Hz, 1H),
3.12–2.99 (m, 2H), 2.84–2.55 (m, 3H), 1.29 (dt, J = 13.3, 7.1 Hz,
3H). 13C NMR (101 MHz, CDCl3) d 172.34, 172.11, 137.50, 137.21,
130.03, 129.40, 128.17, 127.95, 127.18, 127.00, 126.32, 125.14,
66.36, 66.02, 60.78, 60.71, 52.86, 52.12, 49.53, 46.11, 40.95,
to afford product
7 as a yellow oil (234 mg, 95% yield),
½
a 2D5
ꢂ
¼ ꢁ37:8 (c 2.1, CH2Cl2). Lit.10c data: ½a D25
¼ ꢁ27:3 (CH2Cl2)
ꢂ
73% ee.
4.3.11.3. (S)-2-Amino-1-(2-bromophenyl)ethanol.
At first,
Zn powder (1.17 g, 18 mmol) was added to a solution of 7
(0.9 mmol) in ethanol/H2O (12:3, v/v), followed by concentrated
HCl (2.5 mL). The mixture was stirred at room temperature for
4 h. Then, the solution was neutralized by 5 M aqueous NaOH until
the pH = 10, and extracted with ethyl acetate. The organic phase
was dried over anhydrous Na2SO4 and evaporated under reduced
pressure. The crude product was purified by column chromatogra-
phy eluting with dichloromethane and methanol to afford the
product as a pale yellow solid (185 mg, 95% yield).
39.91, 14.24, 14.18. HRMS-ESI (m/z) calcd for
C13H17NO3
[M+Na+]: 258.1106, found: 258.1110.
Acknowledgements
This work was supported by the National Science Foundation of
China (No. 21172082). The Analysis and Testing Centre of Huaz-
hong University of Science and Technology is acknowledged for
the characterization of new compounds.
4.3.11.4.
ole.
(S)-5-(2-Bromophenyl)-4,5-dihydro-2-methyloxaz-
To a stirred milky solution of ethyl acetimidate hydro-
References
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Melloni, G.; Modena, G. J. Org. Chem. 1979, 44, 3022–3028.
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Soc. 2011, 133, 2714–2720.
4.3.11.5.
yl)phenyl)acrylate.
dihydro-2-methyloxazole (150 mg, 0.62 mmol), ethyl acrylate
(530 L), Pd(OAc)2 (15 mg), PPh3 (35 mg), and Et3N (4 mL) was
(2E)-Ethyl-3-(2-((S)-4,5-dihydro-2-methyloxazol-5-
A mixture of (S)-5-(2-bromophenyl)-4,5-
l
stirred at 80 °C for 16 h. The reaction was then cooled to room tem-
perature, diluted with H2O and extracted with CH2Cl2. The organic
phase was dried over anhydrous Na2SO4, filtered and concentrated,
and the crude material was purified by flash chromatography elut-
ing with petroleum ether and ethyl acetate to afford the coupling
product as a yellow oil (78 mg, 50% yield). 1H NMR (400 MHz,
CDCl3) d 7.84 (d, J = 15.7 Hz, 1H), 7.58 (d, J = 7.7 Hz, 1H), 7.45–
7.37 (m, 2H), 7.37–7.31 (m, 1H), 6.36 (d, J = 15.7 Hz, 1H), 5.81
(dd, J = 10.3, 8.1 Hz, 1H), 4.28 (q, J = 7.2 Hz, 2H), 3.64 (ddd,
J = 14.1, 8.1, 1.4 Hz, 1H), 2.12 (t, J = 1.3 Hz, 3H), 1.35 (t, J = 7.1 Hz,
3H). 13C NMR (101 MHz, CDCl3) d 166.42, 164.79, 140.55, 140.00,
131.91, 130.26, 128.23, 127.10, 125.24, 121.28, 77.96, 62.80,
60.67, 14.29, 13.94.
10. (a) Zhou, Y.; Dong, J.; Zhang, F.; Gong, Y. J. Org. Chem. 2011, 76, 588–600; (b)
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Kannan, R.; Rajagopal, G. Tetrahedron: Asymmetry 2011, 22, 857–865; (e) Wei,
Y.; Yao, L.; Zhang, B.; He, W.; Zhang, S. Tetrahedron 2011, 67, 8552–8558; (f)
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43, 5442–5444.
4.3.11.6. Ethyl 2-((4S)-1,2,3,4-tetrahydro-4-hydroxyisoquinolin-
11. Luzzio, F. A.; Okoromoba, O. E. Tetrahedron Lett. 2011, 52, 6530–6533.
12. (a) Lu, D.; Zhou, Y.; Li, Y.; Yan, S.; Gong, Y. J. Org. Chem. 2011, 76, 8869–8878;
(b) Gu, L.; Zhou, Y.; Zhang, J.; Gong, Y. Tetrahedron: Asymmetry 2012, 23, 124–
129.
1-yl)acetate 6a.
product (60 mg, 0.25 mmol) in ethanol was added 3 M HCl
(84 L, 1.0 equiv). After stirring overnight, the solvent was neutral-
To a stirred solution of the above coupling
l