Asymmetric domino double michael addition of nitroolefins and aldehyde esters with trans-perhydroindolic acid as an organocatalyst

Article abstract of DOI:10.1055/s-0033-1338839

An asymmetric domino double Michael addition reaction was developed using accessible substrates to construct biologically important and synthetically challenging cyclopentanes with four contiguous stereocenters. The proline-like molecules, trans-perhydroindolic acids, proved to be efficient organocatalysts in this reaction. Under the optimal reaction conditions, the asymmetric domino double Michael addition provided good yields (up to 98%), and excellent diastereoselectivities (up to 100% dr) and enantioselectivities (up to 99% ee). The obtained polysubstituted aliphatic cyclopentanes not only exist in biologically active natural products and medicines, but can also be converted into many other useful scaffolds via a simple transformation, such as cis-fused bicyclic lactams. Our current methodology is suitable for the synthesis of polysubstituted aliphatic cyclopentanes with contiguous multiple stereocenters. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1338839

1612▌
FEATURE ARTICLE
feature article
Asymmetric Domino Double Michael Addition of Nitroolefins and Aldehyde
Esters with trans-Perhydroindolic Acid as an Organocatalyst
trans-Perhydroindolic Acid as an Organocatalyst
Qianjin An,a Jiefeng Shen,a Nicholas Butt,b Delong Liu,*a Yangang Liu,a Wanbin Zhang*a,b
a
School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. of China
b
School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. of China
Fax +86(21)54743265; E-mail: wanbin@sjtu.edu.cn
Received: 07.03.2013; Accepted after revision: 30.04.2013
In the same year, Zhong also developed an asymmetric
Abstract: An asymmetric domino double Michael addition reac-
domino double Michael reaction and/or domino Michael–
tion was developed using accessible substrates to construct biolog-
Henry reaction for the preparation of functionalized cy-
ically important and synthetically challenging cyclopentanes with
four contiguous stereocenters. The proline-like molecules, trans-
clopentanes with four stereogenic carbons, including two
perhydroindolic acids, proved to be efficient organocatalysts in this quaternary stereocenters.8 Recently, Barbas developed a
reaction. Under the optimal reaction conditions, the asymmetric
domino double Michael addition provided good yields (up to 98%),
highly selective organocatalytic Michael–Henry cascade
reaction that provides spirooxindole core structures with
and excellent diastereoselectivities (up to 100% dr) and enantiose-
four consecutive stereogenic centers in excellent chemical
lectivities (up to 99% ee). The obtained polysubstituted aliphatic
and optical yield.9 The above examples either utilized
cyclopentanes not only exist in biologically active natural products
substrates not easily accessible or provided somewhat low
diastereoselectivities and reaction activities. Thus, the
search for an efficient protocol for the construction of the
less researched polysubstituted cyclopentane with contig-
uous multiple stereocenters from readily accessible sub-
strates is worthy of investigation. We, therefore, utilized
common substrates such as nitroolefins and aldehyde es-
ters for the synthesis of cyclopentanes possessing four ste-
reocenters (Scheme 1).
and medicines, but can also be converted into many other useful
scaffolds via a simple transformation, such as cis-fused bicyclic lac-
tams. Our current methodology is suitable for the synthesis of poly-
substituted aliphatic cyclopentanes with contiguous multiple
stereocenters.
Key words: polysubstituted aliphatic cycloalkanes, trans-perhy-
droindolic acids, organocatalyst, domino double Michael addition,
bicyclic lactam
NO2
R1
Introduction
CO2R2
catalyst
NO2
CO2R2
+
R1
O
Polysubstituted cycloalkanes with contiguous multiple
functionalized stereocenters represent an important class
of substructure widely encountered in bioactive natural
products and medicines.1 They also serve as important in-
termediates in organic synthesis.1b,2 Much research has fo-
cused on the construction of this backbone with the
control of multiple stereocenters. Organocatalytic asym-
metric domino reactions are often used to obtain the afore-
mentioned molecules because the control of multiple
stereocenters can be achieved under mild reaction condi-
tions and concise one-pot operations.3 However, the ma-
jority of methods concern the synthesis of six-membered
cycloalkanes possessing multiple stereocenters in their
backbone.4 Few examples relate to the construction of
five-membered systems,5–9 including those employing
multistep reactions.5,9 In 2007, Wang reported an asym-
metric organocatalytic cascade double Michael addition
reaction in which a cyclopentane backbone could be con-
structed with three stereogenic centers.6 The following
year, the Córdova group developed a series of amino-, for-
myl-, and ester-functionalized cyclopentanes with four
stereocenters (97–99% ee) via a one-pot transformation.7
O
Scheme 1 The present domino reaction
Our group recently disclosed an efficient synthetic route
to trans-perhydroindolic acids, a key intermediate in the
synthesis of trandolapril and its isomers.10 These proline-
like molecules subsequently proved to be excellent or-
ganocatalysts in some asymmetric catalytic reactions.
They not only showed excellent diastereo- and enantiose-
lectivities in asymmetric Michael additions of aldehydes
to nitroolefins (up to 99% de and 98% ee),10a but also ex-
cellent catalytic behavior in asymmetric domino Michael
reactions of aldehyde esters or aldehyde amines with β,γ-
unsaturated α-keto esters.10b,c We therefore envisioned
that they would also be efficient in the reaction as depicted
in Scheme 1.
Results and Discussion
Initially, the use of key intermediate Ia of trandolapril and
its isomers Ib–d were examined in asymmetric domino
double Michael addition reactions (Figure 1). Thus, reac-
tions involving (E)-β-nitrostyrene (1a) and ethyl (E)-6-
SYNTHESIS 2013, 45, 1612–1623
Advanced online publication: 29.05.2013
DOI: 10.1055/s-0033-1338839; Art ID: SS-2013-Z0188-FA
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

FEATURE ARTICLE
trans-Perhydroindolic Acid as an Organocatalyst
1613
Biographical Sketches█
Qianjin An was born in TCM in China, where he ob- the guidance of Prof.
1987 in Zhoukou, Henan tained his bachelor degree in Yangang Liu and Prof.
province of China. He stud- 2010. He is currently a Mas- Zhang Wanbin.
ied Chinese traditional med- ter’s student at Shanghai
icine at Henan University of Jiaotong University, under
Jiefeng Shen was born in sity under the supervision of sity. His current research in-
1979 in Dafeng, Jiangsu Prof. Wanbin Zhang (2012). terests concern organic
province of China. He re- He currently works as a chemistry and pharmaceuti-
ceived his Ph.D. degree in postdoctoral fellow in phar- cal chemistry.
applied chemistry from maceutical chemistry at
Shanghai Jiao Tong Univer- Shanghai Jiao Tong Univer-
Nicholas Butt received his Christopher Moody. He is versity. His current research
Ph.D. in organic chemistry currently working in Profes- interests focus on asymmet-
(2011) from the University sor Wanbin Zhang’s group ric catalysis.
of Nottingham, UK, under as a postdoctoral researcher
the supervision of Professor at Shanghai Jiao Tong Uni-
Delong Liu received his he performed postdoctoral Tong University. His re-
Ph.D. in organic chemistry research in the same re- search interests concern or-
(2007) at Shanghai Jiao search group for two years. ganic synthetic chemistry
Tong University in China He is currently an associate and asymmetric catalysis
under the supervision of professor of pharmaceutical and synthesis.
Professor Wanbin Zhang; chemistry at Shanghai Jiao
Yangang Liu received his at Shanghai Jiao Tong Uni- thesis, and application of
Ph.D. degree in applied versity. From 1999–2000, functional molecular com-
chemistry (1995) at East he performed postdoctoral pounds,
pharmaceutical
China University of Science research at Princeton Uni- synthetic chemistry, and
and Technology. He then versity, USA. Professor asymmetric catalysis and
worked as an associate pro- Liu’s current research inter- synthesis.
fessor and then a professor ests include the design, syn-
Wanbin Zhang received worked as an assistant pro- Engineering of Shanghai
his BS and MS degree from fessor at Osaka University Jiao Tong University. Pro-
East China University of until 2001 and then as a re- fessor Zhang’s current re-
Science and Technology search fellow at the Special- search interests include
(ECUST) in 1985 and 1988 ty Chemicals Research synthetic organic chemistry,
respectively. From 1993– Center of the Mitsubishi asymmetric catalysis and
1997, he undertook Ph.D. Chemical
Corporation. synthesis, and process stud-
studies at Osaka University Since 2003, he has worked ies on pharmaceuticals and
under the supervision of as a professor in the School their intermediates.
Prof. Isao Ikeda. He then of Chemistry and Chemical
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1612–1623

1614
Q. An et al.
FEATURE ARTICLE
Table 1 Effect of Catalyst on the Asymmetric Domino Reactionsa
H
H
H
H
H
NO2
COOH
COOH
COOH
COOH
N
N
N
NO2
H
H
H
H
H
catalyst (10 mol%)
NaHCO3 (1 equiv)
Ph
1a
CO2Et
Ia
Ib
Ic
+
EtOH, r.t.
COOEt
O
O
COOH
2b
COOH
3ab
N
H
N
N
H
H
H
Entry
Cat.
Time (h) Yieldb (%) drc
eed (%)
Id
II
III
O
CH3
1
2
3
4
5
6
7
8
Ia
Ib
Ic
12
12
2
90
12:0:71:17
14:0:70:16
0:0:69:31
0:0:67:33
8:0:71:21
–
44
–45
90
N
Ph
•HCl
90
Ph
OTMS
N
H
t-Bu
N
H
V
98
IV
Id
II
2
98
–90
–34
–
Figure 1
1.5
7d
12
7d
98
III
IV
V
trace
87
oxohex-2-enoate (2b) were performed using Ia–d as or-
ganocatalysts in the presence of sodium hydrogen carbon-
ate in ethanol at room temperature. Details are shown in
Table 1.
0:17:58:25
–
–40
–
trace
a Unless otherwise specified: 1a (0.13 mmol, 1.0 equiv), 2b (0.16
mmol, 1.2 equiv), catalyst (10 mol%), NaHCO3 (1 equiv), 25 °C.
b Isolated yields after silica gel column chromatography.
c Determined by 1H NMR spectra.
To our delight all reactions proceeded smoothly. Catalysts
Ic and Id showed high reaction activities as well as good
diastereo- and enantioselectivity (Table 1, entries 1–4).
As a comparison proline (II) and (S)-indoline-2-carboxyl-
ic acid (III) were also used, but did not provide satisfac-
tory results (entries 5 and 6). The commonly used
Jørgensen–Hayashi proline ether catalyst IV was exam-
ined and low reaction activity and stereoselectivity were
obtained (entry 7). The reaction did not occur when using
a secondary chiral amine V (entry 8). Therefore, we de-
cided to use Ic in subsequent reactions.
d Determined by chiral HPLC with the major configuration.
ther increasing the amount of sodium bicarbonate did not
improve the reaction outcome (entry 12).
We then investigated the influence of solvent on the reac-
tion (Table 3). High yields and good enantioselectivities
were obtained by using protic alcohol solvents, such as
methanol, ethanol, propan-2-ol, and butanol (entries 1–4).
An aprotic solvent, chloroform, proved unsuitable for the
reaction (entry 5). Ethanol was found to be the best sol-
vent according to reaction activity, stereoselectivity, and
enantioselectivity.
With the desired catalyst in hand, our attention turned to
choosing an effective additive for the asymmetric double
Michael addition. Several different additives were used
with the aim of improving the reaction activity. When no
additive or an acidic additive, such as benzoic acid, was
added the reaction proceeded slowly to give 4 (the inter-
mediate of 3ab) as the major product, albeit in high yield
(Table 2, entries 1 and 2). In contrast, when basic addi-
tives were used, the reactions proceeded smoothly to give
3ab as the sole product in excellent yields (entries 3–8).
The use of basic additives also dramatically shortened the
reaction time. Both inorganic and organic basic additives
provided excellent catalytic activity. However, the use of
strong inorganic base is not suitable in this reaction as a
complex mixture of products results (entry 9). Readily
available sodium hydrogen carbonate is somewhat better
than others according to the combination of reaction activ-
ity, chemical yield, and stereoselectivity.
Temperature had an effect on the reaction activity. In-
creasing the reaction temperature to 35 °C resulted in a de-
crease in enantioselectivity and yield (Table 3, entry 6).
When the temperature was decreased to 15 °C, a notable
improvement in enantioselectivity (99%) was observed
(entry 7). Decreasing the temperature further to 0 °C did
not improve the results (entry 8). The optimal reaction
conditions were, therefore, found to be using Ic (10
mol%) in ethanol in the presence of sodium hydrogen car-
bonate (2.0 equiv) at 15 °C.
With the optimal reaction conditions established, the ap-
plicability of the asymmetric domino double Michael re-
action to different substrates was evaluated (Table 4).
Firstly, the influence of the ester group R2 of 2 was exam-
ined. It appears that the size of R2 has a large impact on
the reaction process, with the ethyl group giving the best
result (entries 1–4). Subsequently, nitroolefins possessing
different substituted groups were examined. Excellent en-
antioselectivities and high yields were observed for elec-
The amount of sodium bicarbonate also had an effect on
the reaction. Decreasing the loading from 1.0 equivalent
to 0.5 equivalent reduced reaction activity and diastereo-
selectivity (entry 10). When increasing the loading from
1.0 equivalent to 2.0 equivalents, an obvious improve-
ment was obtained in enantioselectivity (entry 11). Fur-
Synthesis 2013, 45, 1612–1623
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
trans-Perhydroindolic Acid as an Organocatalyst
1615
Table 2 Additive Screening for the Asymmetric Domino Double Michael Addition
NO2
NO2
O
Ic (10 mol%)
Ph
O
1a
additive (1 equiv)
CO2Et
+
+
CO2Et
O2N
EtOH, r.t.
COOEt
O
Ph
2b
3ab
4
Entrya
Time (h)
Additive (%)
Yieldb (%)
drc
eed (%)
1
2
48
72
2
–
95 (3ab + 4)
96 (3ab + 4)
85 (3ab)
80 (3ab)
96 (3ab)
98 (3ab)
93 (3ab)
91 (3ab)
trace
10:90 (3/4)e,f
6:94 (3/4)e,f
0:0:62:38
0:0:68:32
0:0:75:25
0:0:69:31
13:0:57:30
16:16:45:23
–
n.d.
n.d.
93
87
88
90
85
77
–
benzoic acid
DABCO
TMEDA
NaOAc
NaHCO3
KHCO3
Na2CO3
NaOH
3
4
2
5
2
6
2
7
2
8
2
9
2
10g
11h
12i
10
2
NaHCO3
NaHCO3
NaHCO3
94 (3ab)
97 (3ab)
90 (3ab)
38:0:62:0
20:0:60:20
13:0:74:13
91
93
90
2
a Unless otherwise specified: 1a (0.13 mmol, 1.0 equiv), 2b (0.16 mmol, 1.2 equiv), Ic (10 mol%), additive (1 equiv), 25 °C.
b Isolated yields after silica gel column chromatography.
c Determined by 1H NMR spectra.
d Determined by chiral HPLC with the major configuration.
e The ratio of 3 and 4 was determined by 1H NMR spectra.
f The absolute configuration of 4 is determined according to that of 3.
g NaHCO3 (0.5 equiv) was used.
h NaHCO3 (2.0 equiv) was used.
i NaHCO3 (3.0 equiv) was used.
tron-withdrawing aromatic nitroolefins (entries 5–10). methane and petroleum ether. X-ray crystal structure anal-
Similarly, aromatic nitroolefins with electron-donating ysis shows that the nitro, ester, and formyl groups lie on
groups also provided excellent asymmetric catalytic re- the same side of the five-member ring, while the tert-butyl
sults (entries 11 and 12). When the phenyl ring was re- group points to the opposite side (Figure 2).11
placed by either naphthalene, furan, or thiophene rings,
excellent catalytic activity was also observed (entries 13–
16). Specifically, the use of an aliphatic isopropyl back-
bone gives rise to almost quantitative diastereoselectivity
and excellent enantioselectivity (entry 17). Inspired by
these results, several aliphatic nitroolefins were utilized.
All showed excellent applicability to the reaction condi-
tions, although a different ester group R2 of 2 was used
(entries 18–26). This methodology is convenient and effi-
cient for the construction of polysubstituted aliphatic cy-
cloalkanes with contiguous multiple stereocenters.
Figure 2 Single crystal of enantioenriched 3pd
To determine the absolute configuration of the asymmet-
ric domino double Michael addition products, X-ray crys-
tallography studies were performed. A single crystal of
the corresponding polysubstituted aliphatic cycloalkane
3pd was obtained via recrystallization from dichloro-
A transition-state model was proposed to account for the
stereochemical outcome when using Ic as a catalyst
(Scheme 2). The conjugated aldehyde ester 2b reacts with
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1612–1623

1616
Q. An et al.
FEATURE ARTICLE
Table 3 Effect of Solvent and Temperature on Asymmetric Domino Reactions
NO2
Ic (10 mol%)
NaHCO3 (2 equiv)
Ph
O
NO2
CO2Et
+
COOEt
O
2b
1a
3ab
Entrya
Solvent
Temp (°C)
Time (h)
Yieldb (%)
drc
eed (%)
1
2
3
4
5
6
7
8
MeOH
EtOH
i-PrOH
BuOH
CHCl3
EtOH
EtOH
EtOH
25
25
25
25
25
35
15
0
5
89
97
90
90
88
93
98
90
34:0:48:18
20:0:60:20
13:0:66:21
38:0:62:0
7:0:69:24
0:0:63:37
8:0:60:32
40:0:43:17
74
93
89
89
62
79
99
92
2
6
6
3d
1.5
4
12
a Unless otherwise specified: 1a (0.13 mmol, 1.0 equiv), 2b (0.16 mmol, 1.2 equiv), Ic (10 mol%), NaHCO3 (2 equiv).
b Isolated yields after silica gel column chromatography.
c Determined by 1H NMR spectra.
d Determined by chiral HPLC with the major configuration.
Ic to give a nucleophilic enamine intermediate, whilst (E)- the plane of the alkene, followed by subsequent cycliza-
β-nitrostyrene (1a) is directed toward the carboxylic acid tion to the conjugated ester. The final product was then re-
group from above by a hydrogen bond, which enhances leased after the hydrolysis process with the shown
the electrophilic character of 1a. The resulting enamine configuration.
attacks the carbon–carbon double bond of 1a from behind
Table 4 Asymmetric Double Michael Reaction with Different Nitroolefins and Aldehyde Esters
NO2
Ic (10 mol%)
NaHCO3 (2 equiv)
R1
CO2R2
NO2
CO2R2
+
R1
O
EtOH, 15 °C
1
2
O
3
Entrya
R1
R2
Time
Yieldb (%)
Product
drc
eed (%)
1
2
Ph
Me
Et
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
6 h
4 h
95
98
90
93
94
91
95
93
90
97
90
3aa
3ab
3ac
3ad
3b
15:8:54:23
7:0:62:31
12:0:63:25
17:17:17:49
20:0:80:0
50:0:50:0
7:0:60:33
12:0:75:13
7:0:64:29
50:0:50:0
25:0:63:12
97
99
85
99
92
99
99
99
96
96
97
Ph
3
Ph
t-Bu
Bn
Et
4
Ph
5
2-ClC6H4
3-ClC6H4
4-BrC6H4
4-FC6H4
4-F3CC6H4
6
Et
3c
7
Et
3d
8
Et
3e
9
Et
3f
10
11
2,6-Cl2C6H3
3-MeOC6H4
Et
3g
Et
3h
Synthesis 2013, 45, 1612–1623
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
trans-Perhydroindolic Acid as an Organocatalyst
1617
Table 4 Asymmetric Double Michael Reaction with Different Nitroolefins and Aldehyde Esters (continued)
NO2
Ic (10 mol%)
NaHCO3 (2 equiv)
R1
CO2R2
NO2
CO2R2
+
R1
O
EtOH, 15 °C
1
2
O
3
Entrya
R1
R2
Time
Yieldb (%)
Product
drc
eed (%)
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
3,4-(MeO)2C6H3
1-naphthyl
2-naphthyl
2-furyl
2-thienyl
i-Pr
Et
6 h
4 h
4 h
4 h
4 h
8 h
8 h
4 d
4 d
4 d
7 d
8 h
8 h
12 h
8 h
95
88
90
96
98
82
85
80
78
75
74
85
82
80
84
3i
25:0:75:0
12:13:75:0
11:0:56:33
17:49:17:17
12:13:50:25
0:0:100:0
0:0:100:0
0:0:100:0
0:0:100:0
0:0:100:0
0:0:100:0
0:0:100:0
0:0:100:0
0:0:100:0
0:0:100:0
99
99
99
89
99
96
94
96
95
91
91
93
99
94
95
Et
3j
Et
3k
Et
3l
Et
3m
3n
Et
CHEt2
t-Bu
Et
3o
Me
Et
3pa
3pb
3pc
3pd
3qa
3qb
3qc
3qd
t-Bu
t-Bu
t-Bu
Bn
Me
Et
t-Bu
Cy
Cy
Cy
t-Bu
Bn
Cy
a Unless otherwise specified: 1 (0.13 mmol, 1.0 equiv), 2 (0.16 mmol, 1.2 equiv), Ic (10 mol%), NaHCO3 (2 equiv), 15 °C.
b Isolated yields after silica gel column chromatography.
c Determined by 1H NMR spectra.
d Determined by chiral HPLC with the major configuration.
NO2
Ph
CO2Et
NO2
+
COOEt
O
Ph
H
H
1a
2b
O
COOH
3ab
N
H
Ic
Ic
Ic
H2O
H2O
O
O
O
OH
O
N
O
N
N
Ph
N
N
Ph
H
H
O
O
NO2
O
O
CO2Et
CO2Et
CO2Et
Scheme 2 Proposed pathway for the stereochemical outcome
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1612–1623

1618
Q. An et al.
FEATURE ARTICLE
Methyl 2-[(1R,2S,3R,4R)-4-Formyl-2-nitro-3-phenylcyclopen-
tyl]acetate (3aa)
Pale yellow oil; yield: 36.0 mg (95%); HPLC (Chiralcel AS-H, hex-
ane–i-PrOH, 98:2, 210 nm, 0.5 mL·min–1): tR = 76.77 (major), 83.32
min (minor); 97% ee.
The polysubstituted aliphatic cycloalkanes with contigu-
ous multiple stereocenters 3 have the potential to partici-
pate in a variety of transformations. For example,
reduction and intramolecular lactonization of adduct 3ab
with sodium borohydride and nickel(II) chloride hexahy-
drate afforded the corresponding cis-fused bicyclic lactam
5 in good yields (85%) (Scheme 3). Structures such as 5
are not only pharmaceutically interesting, but also repre-
sent a synthetically challenging family of compounds ow-
ing to the presence of four stereogenic centers.3
[α]D25 +23.0 (c 0.2, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 9.76 (d, J = 1.6 Hz, 1 H), 7.37–
7.33 (m, 2 H), 7.30–7.26 (m, 1 H), 7.21–7.19 (m, 2 H), 5.14 (dd, J =
8.0, 4.0 Hz, 1 H), 4.24 (dd, J = 8.0, 4.0 Hz, 1 H), 3.69 (s, 3 H), 3.16–
3.05 (m, 2 H), 2.49–2.40 (m, 3 H), 2.11–2.02 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 197.4, 169.1, 137.4, 127.0, 125.6,
124.8, 92.9, 55.7, 49.7, 47.9, 38.2, 31.5, 29.3.
NO2
Ph
H
HRMS (ESI): m/z [M + H]+ calcd for C15H18NO5: 292.1185; found:
292.1184.
H
Ph
NaBH4, NiCl2•6H2O
N
CO2Et
O
MeOH, 0 °C to r.t.
85%
HO
Ethyl 2-[(1R,2S,3R,4R)-4-Formyl-2-nitro-3-phenylcyclopen-
tyl]acetate (3ab)
Pale yellow oil; yield: 39.0 mg (98%); HPLC (Chiralcel AD-H,
hexane–i-PrOH, 97:3, 210 nm, 0.5 mL·min–1): tR = 75.94 min (ma-
jor); >99% ee.
H
O
3ab
5
Scheme 3 The synthesis of the pyrrolidinone-containing bicyclic
compounds
[α]D25 +56.4 (c 0.1, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 9.77 (d, J = 1.6 Hz, 1 H), 7.40–
7.32 (m, 2 H), 7.32–7.28 (m, 1 H), 7.24–7.16 (m, 2 H), 5.15 (dd, J =
8.0, 4.0 Hz, 1 H), 4.25 (dd, J = 8.0, 4.0 Hz, 1 H), 4.19–4.13 (m, 2
H), 3.15–3.09 (m, 2 H), 2.48–2.40 (m, 3 H), 2.13–2.01 (m, 1 H),
1.26 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 200.0, 171.2, 140.0, 129.6, 128.1,
127.4, 95.5, 61.3, 58.3, 50.6, 40.8, 34.3, 31.9, 14.4.
In summary, we have developed an asymmetric domino
double Michael addition utilizing accessible substrates to
construct biologically important and synthetically chal-
lenging cyclopentanes with four contiguous stereocenters.
The proline-like molecules, trans-perhydroindolic acids,
proved to be efficient organocatalysts for this reaction.
Under the optimal reaction conditions, the asymmetric
domino double Michael addition occurred with excellent
catalytic behavior in good yields (up to 98%), and excel-
lent diastereoselectivities (up to 100%) and enantioselec-
tivities (up to 99%). These terminal products not only
exist in biologically active natural products and medi-
cines, but can also be converted into many other useful
scaffolds, such as cis-fused bicyclic lactams, via a simple
transformation. Our methodology is suitable for the syn-
thesis of polysubstituted aliphatic cycloalkanes with mul-
tiple stereocenters.
HRMS (ESI): m/z [M + Na]+ calcd for C16H19NO5Na: 328.1161;
found: 328.1185.
tert-Butyl 2-[(1R,2S,3R,4R)-4-Formyl-2-nitro-3-phenylcyclo-
pentyl]acetate (3ac)
Pale yellow oil; yield: 38.9 mg (90%); HPLC (Chiralcel IC-3, hex-
ane–i-PrOH, 88:12, 210 nm, 0.35 mL·min–1): tR = 27.16 (major),
32.85 min (minor); 85% ee.
[α]D25 +25.3 (c 0.32, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 9.77 (d, J = 1.6 Hz, 1 H), 7.39–
7.27 (m, 3 H), 7.23–7.18 (m, 2 H), 5.15 (dd, J = 8.0, 4.0 Hz, 1 H),
4.24 (dd, J = 8.0, 4.0 Hz, 1 H), 3.36 (d, J = 12.2 Hz, 1 H), 3.15–3.01
(m, 2 H), 2.45–2.32 (m, 1 H), 2.14–1.98 (m, 2 H), 1.45 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 200.1, 170.4, 140.1, 129.5, 128.1,
127.4, 95.6, 58.4, 50.6, 41.1, 35.4, 31.9, 28.4, 28.2.
HRMS (ESI): m/z [M + H]+ calcd for C18H24NO5: 334.1654; found:
334.1653.
1H (400 MHz) and 13C NMR (100 MHz) spectra were recorded on
a Varian Mercury Plus-400 spectrometer with TMS as internal stan-
dard. HRMS was performed at the Analysis Center of Shanghai Jiao
Tong University. Enantioselectivity was measured by HPLC using
Daicel Chiralcel AD-H, AS-H, and IC-3-H columns (hexane–i-
PrOH). Column chromatography was performed using 100–200
mesh silica gel. Melting points were measured with an SGW X-4
micro melting point apparatus. All commercially available sub-
strates were used as received. Nitroolefins were prepared according
to literature procedures.12
Benzyl 2-[(1R,2S,3R,4R)-4-Formyl-2-nitro-3-phenylcyclopen-
tyl]acetate (3ad)
Pale yellow oil; yield: 44.3 mg (93%); HPLC (Chiralcel AS-H, hex-
ane–i-PrOH, 90:10, 210 nm, 0.3 mL·min–1): tR = 80.31 min (major);
>99% ee.
[α]D25 +12.3 (c 0.12, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 9.76 (d, J = 1.6 Hz, 1 H), 7.41–
7.27 (m, 8 H), 7.19 (d, J = 7.2 Hz, 2 H), 5.17–5.12 (m, 3 H), 4.25
(dd, J = 8.0, 4.0 Hz, 1 H), 3.18–3.05 (m, 2 H), 2.51 (d, J = 7.4 Hz,
2 H), 2.47–2.36 (m, 1 H), 2.12–2.01 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 197.4, 168.5, 137.4, 133.0, 126.9,
126.3, 126.1, 125.9, 125.5, 124.8, 92.9, 64.6, 55.7, 47.9, 38.2, 31.7,
29.3.
Asymmetric Domino Double Michael Addition; General Proce-
dure
The catalyst Ic (2.3 mg, 0.013 mmol), NaHCO3 (21.8 mg, 0.26
mmol), and aldehyde ester (0.16 mmol) were dissolved in EtOH (1
mL) at 15 °C. The solution was stirred for 5 min, and then the ap-
propriate nitroolefin (0.13 mmol) was added. The mixture was
stirred at 15 °C until complete consumption of nitroolefin (TLC
monitoring). The solvent was then evaporated and the crude product
was purified by flash column chromatography (silica gel, PE–
EtOAc, 10:1) to provide the corresponding Michael adducts. Dia-
stereoselectivities were measured by 1H NMR analysis of the crude
product. The ee was determined by HPLC analysis of samples with
major configuration of the samples.
HRMS (ESI): m/z [M + H]+ calcd for C21H22NO5: 368.1498; found:
368.1504.
Synthesis 2013, 45, 1612–1623
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
trans-Perhydroindolic Acid as an Organocatalyst
1619
Ethyl 2-[(1R,2S,3R,4R)-3-(2-Chlorophenyl)-4-formyl-2-nitro-
cyclopentyl]acetate (3b)
Pale yellow oil; yield: 41.4 mg 94%); HPLC (Chiralcel IC-3, hex-
ane–i-PrOH, 90:10, 210 nm, 0.4 mL·min–1): tR = 27.16 (minor),
32.85 min (major); 92% ee.
Ethyl 2-{(1R,2S,3R,4R)-4-Formyl-2-nitro-3-[4-(trifluorometh-
yl)phenyl]cyclopentyl}acetate (3f)
Pale yellow oil; yield: 43.8 mg (90%); HPLC (Chiralcel IC-3, hex-
ane–i-PrOH, 88:12, 210 nm, 0.3 mL·min–1): tR = 23.41 (major),
24.85 min (minor); 96% ee.
[α]D25 –35.0 (c 0.16, CH2Cl2).
[α]D25 +22.3 (c 0.26, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 9.79 (d, J = 1.6 Hz, 1 H), 7.42–
7.18 (m, 4 H), 5.19 (dd, J = 8.0, 4.0 Hz, 1 H), 4.69 (dd, J = 8.0, 4.0
Hz, 1 H), 4.19–4.12 (m, 2 H), 3.28–3.22 (m, 1 H), 3.18–3.10 (m, 1
H), 2.48–2.39 (m, 3 H), 2.13–2.04 (m, 1 H), 1.26 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 200.1, 171.2, 136.7, 134.0, 130.7,
129.5, 129.1, 127.9, 94.5, 61.3, 56.5, 48.2, 40.6, 34.2, 31.9, 14.3.
1H NMR (400 MHz, CDCl3): δ = 9.68 (d, J = 2.0 Hz, 1 H), 7.57 (d,
J = 8.4 Hz, 2 H), 7.33 (d, J = 8.4 Hz, 2 H), 5.12 (dd, J = 8.0, 4.0 Hz,
1 H), 4.17 (q, J = 7.2 Hz, 2 H), 4.02–3.97 (m, 1 H), 3.86–3.77 (m, 1
H), 3.37–3.29 (m, 1 H), 2.70–2.56 (m, 3 H), 1.79–1.71 (m, 1 H),
1.26 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 200.0, 171.1, 138.5, 128.6, 126.1,
109.9, 95.2, 61.5, 53.9, 50.4, 40.2, 37.9, 32.2, 14.3.
HRMS (ESI): m/z [M + H]+ calcd for C17H19NO5F3: 374.1215;
HRMS (ESI): m/z [M + H]+ calcd for C16H19NO5Cl: 340.0952;
found: 340.0981.
found: 374.1205.
Ethyl 2-[(1R,2S,3R,4R)-3-(3-Chlorophenyl)-4-formyl-2-nitro-
cyclopentyl]acetate (3c)
Pale yellow oil; yield: 40.2 mg (91%); HPLC (Chiralcel AD-H,
hexane–i-PrOH, 97:3, 210 nm, 0.5 mL·min–1): tR = 124.10 min (ma-
jor); >99% ee.
Ethyl 2-[(1R,2S,3R,4R)-3-(2,6-Dichlorophenyl)-4-formyl-2-ni-
trocyclopentyl]acetate (3g)
Pale yellow solid; yield: 47.1 mg (97%); mp 106–107 °C; HPLC
(Chiralcel IC-3, hexane–i-PrOH, 94:6, 210 nm, 0.6 mL·min–1): tR =
36.77 (major), 40.51 min (minor); 96% ee.
[α]D25 +42.7 (c 0.12, CH2Cl2).
[α]D25 +50.5 (c 0.4, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 9.75 (d, J = 1.6 Hz, 1 H), 7.28–
7.26 (m, 2 H), 7.19 (s, 1 H), 7.10–7.08 (m, 1 H), 5.13 (dd, J = 8.0,
4.0 Hz, 1 H), 4.24 (dd, J = 8.0, 4.0 Hz, 1 H), 4.19–4.11 (m, 2 H),
3.15–3.04 (m, 2 H), 2.51–2.40 (m, 3 H), 2.11–1.98 (m, 1 H), 1.26 (t,
J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 199.5, 171.2, 141.9, 135.3, 130.8,
128.4, 127.6, 125.8, 95.1, 61.4, 58.3, 49.8, 40.8, 34.2, 31.9, 14.4.
1H NMR (400 MHz, CDCl3): δ = 9.71 (d, J = 2.8 Hz, 1 H), 7.34 (d,
J = 8.0 Hz, 2 H), 7.19 (dd, J = 10.8, 5.2 Hz, 1 H), 5.57 (dd, J = 8.0,
4.0 Hz, 1 H), 5.27 (dd, J = 10.8, 5.4 Hz, 1 H), 4.20–4.10 (m, 2 H),
3.60–3.52 (m, 1 H), 3.48–3.38 (m, 1 H), 2.49–2.36 (m, 3 H), 2.12–
2.03 (m, 1 H), 1.26 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 200.1, 171.2, 133.3, 130.3, 130.2,
130.0, 129.4, 93.1, 61.4, 55.9, 47.1, 40.4, 34.3, 32.9, 14.4.
HRMS (ESI): m/z [M + Na]+ calcd for C16H17NNaO5Cl2: 396.0381;
HRMS (ESI): m/z [M + H]+ calcd for C16H19NO5Cl: 340.0952;
found: 340.0955.
found: 396.0375.
Ethyl 2-[(1R,2S,3R,4R)-3-(4-Bromophenyl)-4-formyl-2-nitrocy-
clopentyl]acetate (3d)
Pale yellow oil; yield: 47.3 mg (95%); HPLC (Chiralcel IC-3, hex-
ane–i-PrOH, 88:12, 210 nm, 0.4 mL·min–1): tR = 19.689 (minor),
20.775 min (major); 99% ee.
Ethyl 2-[(1R,2S,3R,4R)-4-Formyl-3-(3-methoxyphenyl)-2-ni-
trocyclopentyl]acetate (3h)
Pale yellow oil; yield: 39.2 mg (90%); HPLC (Chiralcel AD-H,
hexane–i-PrOH, 94: 6, 210 nm, 0.6 mL·min–1): tR = 91.09 (minor),
105.56 min (major); 97% ee.
[α]D25 +42.6 (c 0.3, CH2Cl2).
[α]D25 +16.6 (c 0.18, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 9.75 (d, J = 1.2 Hz, 1 H), 7.48 (d,
J = 8.4 Hz, 2 H), 7.09 (d, J = 8.4 Hz, 2 H), 5.11 (dd, J = 8.0, 4.0 Hz,
1 H), 4.22 (dd, J = 8.0, 4.0 Hz, 1 H), 4.19–4.11 (m, 2 H), 3.13–3.02
(m, 2 H), 2.48–2.41 (m, 3 H), 2.05 (q, J = 12.0 Hz, 1 H), 1.26 (t, J =
7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 199.5, 171.1, 138.9, 132.6, 129.1,
122.1, 95.1, 61.4, 58.3, 49.8, 40.8, 34.2, 31.9, 14.4.
1H NMR (400 MHz, CDCl3): δ = 9.76 (d, J = 1.6 Hz, 1 H), 7.28–
7.24 (m, 1 H), 6.83–6.76 (m, 2 H), 6.75–6.72 (m, 1 H), 5.14 (dd, J =
8.0, 4.0 Hz, 1 H), 4.21 (dd, J = 8.0, 4.0 Hz, 1 H), 4.18–4.12 (m, 2
H), 3.79 (s, 3 H), 3.15–3.05 (m, 2 H), 2.45–2.38 (m, 3 H), 2.10–2.01
(m, 1 H), 1.26 (t, J = 7.2 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ
= 200.0, 171.2, 160.4, 141.5, 130.6, 119.4, 113.6, 113.1, 95.5, 61.3,
58.2, 55.5, 50.5, 40.8, 34.3, 31.9, 14.4.
HRMS (ESI): m/z [M + Na]+ calcd for C16H18NO5NaBr: 406.0266;
found: 406.0260.
HRMS (ESI): m/z [M + H]+ calcd for C17H22NO6: 336.1451; found:
336.1447.
Ethyl 2-[(1R,2S,3R,4R)-3-(4-Fluorophenyl)-4-formyl-2-nitrocy-
clopentyl]acetate (3e)
Pale yellow oil; yield: 39.1 mg (93%); HPLC (Chiralcel IC-3, hex-
ane–i-PrOH, 90:10, 210 nm, 0.4 mL·min–1): tR = 32.73 min (major);
>99% ee.
Ethyl 2-[(1R,2S,3R,4R)-4-Formyl-3-(3,4-dimethoxyphenyl)-2-
nitrocyclopentyl]acetate (3i)
Pale yellow oil; yield: 45.2 mg (95%); HPLC (Chiralcel AD-H,
hexane–i-PrOH, 90:10, 210 nm, 0.6 mL·min–1): tR = 69.79 min (ma-
jor); >99% ee.
[α]D25 +30.0 (c 0.3, CH2Cl2).
[α]D25 +36.4 (c 0.26, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 9.75 (d, J = 1.6 Hz, 1 H), 7.19–
7.16 (m, 2 H), 7.06–7.01 (m, 2 H), 5.11 (dd, J = 8.0, 4.0 Hz, 1 H),
4.23 (dd, J = 8.0, 4.0 Hz, 1 H), 4.20–4.12 (m, 2 H), 3.15–3.04 (m, 2
H), 2.48–2.39 (m, 3 H), 2.09–2.00 (m, 1 H), 1.26 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 199.8, 171.2, 163.6, 161.2, 135.7,
129.1, 129.0, 116.6, 116.4, 95.5, 61.4, 58.5, 49.7, 40.7, 34.2, 31.9,
14.4.
1H NMR (400 MHz, CDCl3): δ = 9.75 (d, J = 1.6 Hz, 1 H), 6.82 (d,
J = 8.4 Hz, 1 H), 6.73 (dd, J = 8.0, 4.0 Hz, 1 H), 6.68 (d, J = 2.0 Hz,
1 H), 5.11 (dd, J = 8.0, 4.0 Hz, 1 H), 4.19–4.12 (m, 3 H), 3.87 (s, 3
H), 3.85 (s, 3 H), 3.14–3.04 (m, 2 H), 2.44 (d, J = 7.2 Hz, 2 H), 2.42–
2.37 (m, 1 H), 2.05 (dd, J = 23.0, 12.2 Hz, 1 H), 1.25 (t, J = 7.2 Hz,
3 H).
13C NMR (100 MHz, CDCl3): δ = 200.3, 171.3, 149.6, 148.9, 132.3,
119.1, 111.8, 110.7, 95.7, 61.3, 58.2, 56.2, 50.4, 40.6, 34.3, 31.9,
14.4.
HRMS (ESI): m/z [M + H]+ calcd for C16H19NO5F: 324.1247;
found: 324.1255.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1612–1623

1620
Q. An et al.
FEATURE ARTICLE
HRMS (ESI): m/z [M + H]+ calcd for C18H24NO7: 366.1553; found:
366.1547.
(m, 2 H), 2.48–2.41 (m, 3 H), 2.08–1.96 (m, 1 H), 1.26 (t, J = 7.2
Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 199.6, 171.1, 142.9, 127.7, 125.5,
125.4, 95.6, 61.4, 58.9, 45.5, 40.2, 34.2, 31.5, 14.4.
HRMS (ESI): m/z [M + H]+ calcd for C14H18NO5S: 312.0906;
found: 312.0901.
Ethyl 2-[(1R,2S,3R,4R)-4-Formyl-3-(naphthalen-1-yl)-2-nitro-
cyclopentyl]acetate (3j)
Pale yellow oil; yield: 40.7 mg (88%); HPLC (Chiralcel IC-3, hex-
ane–i-PrOH, 88:12, 210 nm, 0.3 mL·min–1): tR = 38.70 (major),
40.97 min (minor); >99% ee.
Ethyl 2-[(1R,2S,3S,4R)-4-Formyl-3-isopropyl-2-nitrocyclopen-
tyl]acetate (3n)
Pale yellow oil; yield: 28.8 mg (82%); HPLC (Chiralcel AD-H,
hexane–i-PrOH, 95:5, 210 nm, 0.5 mL·min–1): tR = 22.36 (major),
53.46 min (minor); 96% ee.
[α]D25 +10.0 (c 0.2, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 9.84 (s, 1 H), 8.02 (d, J = 8.2 Hz,
1 H), 7.89 (d, J = 7.8 Hz, 1 H), 7.82 (d, J = 8.0 Hz, 1 H), 7.56 (dt,
J = 14.6, 6.8 Hz, 2 H), 7.47 (t, J = 7.6 Hz, 1 H), 7.36 (d, J = 7.2 Hz,
1 H), 5.14 (d, J = 5.6 Hz, 2 H), 4.16–4.12 (m, 2 H), 3.45–3.39 (m, 1
H), 3.24–3.14 (m, 1 H), 2.63–2.54 (m, 1 H), 2.47 (d, J = 7.4 Hz, 2
H), 2.20 (dd, J = 23.0, 10.8 Hz, 1 H), 1.25 (t, J =7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 200.4, 171.3, 135.9, 134.3, 131.2,
129.5, 129.0, 127.4, 126.5, 125.6, 124.2, 122.8, 95.7, 61.3, 57.3,
45.9, 40.6, 34.3, 31.8, 14.7.
[α]D25 –14.5 (c 0.4, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 9.68 (d, J = 2.8 Hz, 1 H), 4.93 (dd,
J = 7.2, 2.4 Hz, 1 H), 4.18–4.08 (m, 2 H), 3.39–3.30 (m, 1 H), 2.83–
2.78 (m, 1 H), 2.71–2.67 (m, 1 H), 2.37 (dd, J = 7.2, 1.6 Hz, 2 H),
2.20–2.12 (m, 1 H), 2.03–1.97 (m, 1 H), 1.75 (dd, J = 13.6, 6.8 Hz,
1 H), 1.24 (t, J = 7.2 Hz, 3 H), 0.94 (dd, J = 12.8, 6.4 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 201.3, 170.7, 92.6, 61.2, 54.5,
52.6, 41.0, 34.0, 32.0, 31.4, 20.5, 20.3, 14.3.
HRMS (ESI): m/z [M + Na]+ calcd for C20H21NO5Na: 378.1317;
found: 378.1315.
Ethyl 2-[(1R,2S,3R,4R)-4-Formyl-3-(naphthalen-2-yl)-2-nitro-
cyclopentyl]acetate (3k)
White solid; yield: 41.6 mg (90%); mp 99–101 °C; HPLC (Chiralcel
IC-3, hexane–i-PrOH, 86:14, 210 nm, 0.3 mL·min–1): tR = 37.01
(minor), 38.62 min (major); >99% ee.
HRMS (ESI): m/z [M + Na]+ calcd for C13H21NO5Na: 294.1317;
found: 294.1314.
Ethyl 2-[(1R,2S,3S,4R)-4-Formyl-2-nitro-3-(pentan-3-yl)cyclo-
pentyl]acetate (3o)
Pale yellow oil; yield: 32.9 mg (85%); HPLC (Chiralcel AD-H,
hexane–i-PrOH, 97:3, 210 nm, 0.4 mL·min–1): tR = 25.59 (major),
38.11 min (minor); 94% ee.
[α]D25 +45.3 (c 0.3, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 9.81 (d, J = 1.6 Hz, 1 H), 7.86 (d,
J = 8.4 Hz, 1 H), 7.83–7.79 (m, 2 H), 7.66 (s, 1 H), 7.53–7.46 (m, 2
H), 7.30 (dd, J = 8.4, 2.0 Hz, 1 H), 5.26 (dd, J = 8.0, 4.0 Hz, 1 H),
4.43 (dd, J = 8.0, 4.0 Hz, 1 H), 4.21–4.11 (m, 2 H), 3.28–3.14 (m, 2
H), 2.53–2.44 (m, 3 H), 2.12 (dd, J = 23.0, 12.4 Hz, 1 H), 1.27 (t,
J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 200.1, 171.3, 137.1, 133.5, 132.9,
129.7, 128.0, 127.9, 127.0, 126.7, 126.4, 125.0, 95.5, 61.4, 58.3,
50.7, 40.9, 34.3, 32.0, 14.4.
[α]D25 –15.2 (c 0.2, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 9.68 (d, J = 3.0 Hz, 1 H), 4.95 (dd,
J = 7.2, 2.8 Hz, 1 H), 4.14 (dd, J = 7.2, 4.2 Hz, 2 H), 3.08 (dd, J =
5.2, 2.6 Hz, 1 H), 2.72–2.69 (m, 2 H), 2.38 (dd, J = 7.2, 2.4 Hz, 2
H), 2.18–2.13 (m, 1 H), 2.04–1.95 (m, 1 H), 1.40–1.28 (m, 5 H),
1.25–1.23 (m, 3 H), 0.87 (m, 6 H).
13C NMR (100 MHz, CDCl3): δ = 201.4, 171.3, 92.6, 61.2, 54.5,
48.4, 44.0, 41.2, 34.0, 32.1, 23.4, 22.9, 14.3 11.4, 11.3.
HRMS (ESI): m/z [M + Na]+ calcd for C20H21NO5Na: 378.1317;
found: 378.1335.
HRMS (ESI): m/z [M + H]+ calcd for C15H26NO5: 300.1811; found:
300.1814.
Ethyl 2-[(1R,2S,3S,4R)-4-Formyl-3-(furan-2-yl)-2-nitrocyclo-
pentyl]acetate (3l)
Pale yellow oil; yield: 36.7 mg (96%); HPLC (Chiralcel IC-3,
hexane–i-PrOH, 95:5, min–1): tR = 35.52 (minor), 39.30 min
(major); 89% ee.
Methyl 2-[(1R,2S,3R,4R)-3-tert-Butyl-4-formyl-2-nitrocyclo-
pentyl]acetate (3pa)
White solid; yield: 28.2 mg (80%); mp 37–38 °C; HPLC (Chiralcel
AD-H, hexane–i-PrOH, 95:5, 210 nm, 0.4 mL·min–1): tR = 25.41
(major), 28.03 min (minor); 96% ee.
[α]D25 +34.0 (c 0.2, CH2Cl2).
[α]D25 –11.4 (c 0.14, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 9.79 (d, J = 1.4 Hz, 1 H), 7.35 (dd,
J = 1.6, 0.8 Hz, 1 H), 6.30 (dd, J = 3.2, 1.6 Hz, 1 H), 6.19–6.16 (m,
1 H), 5.17 (dd, J = 8.0, 4.0 Hz, 1 H), 4.34 (dd, J = 8.0, 4.0 Hz, 1 H),
4.19–4.09 (m, 2 H), 3.22–3.16 (m, 1 H), 3.12–3.03 (m, 1 H), 2.45–
2.37 (m, 3 H), 2.03–1.94 (m, 1 H), 1.25 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 199.8, 171.2, 152.1, 143.1, 110.8,
107.2, 92.9, 61.3, 55.4, 43.6, 40.5, 34.1, 31.2, 14.4.
1H NMR (400 MHz, CDCl3): δ = 9.66 (d, J = 3.2 Hz, 1 H), 4.98 (dd,
J = 7.2, 2.4 Hz, 1 H), 3.68 (s, 3 H), 2.86 (dd, J = 8.0, 2.6 Hz, 1 H),
2.81–2.73 (m, 1 H), 2.70–2.58 (m, 1 H), 2.37 (dd, J = 7.2, 1.8 Hz, 2
H), 2.17–2.11 (m, 1 H), 2.04–1.98 (m, 1 H), 0.92 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 201.4, 171.7, 92.2, 56.4, 52.9,
52.2, 41.5, 33.7, 33.3, 32.4, 27.6.
HRMS (ESI): m/z [M + Na]+ calcd for C13H21NO5Na: 294.1317;
found: 294.1312.
HRMS (ESI): m/z [M + H]+ calcd for C14H18NO6: 296.1134; found:
296.1126.
Ethyl 2-[(1R,2S,3R,4R)-3-tert-Butyl-4-formyl-2-nitrocyclopen-
tyl]acetate (3pb)
White solid; yield: 29.0 mg (78%); mp 45–46 °C; HPLC (Chiralcel
AD-H, hexane–i-PrOH, 97:3, 210 nm, 0.5 mL·min–1): tR = 23.26
(major), 27.09 min (minor); 95% ee.
Ethyl 2-[(1R,2S,3S,4R)-4-Formyl-2-nitro-3-(thiophen-2-yl)cy-
clopentyl]acetate (3m)
Pale yellow oil; yield: 39.7 mg (98%); HPLC (Chiralcel AD-H,
hexane–i-PrOH, 94:6, 210 nm, 0.5 mL·min–1): tR = 77.14 min (ma-
jor); 99% ee.
[α]D25 –27.1 (c 0.14, CH2Cl2).
[α]D25 +14.0 (c 0.2, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 9.67 (d, J = 3.2 Hz, 1 H), 4.99 (dd,
J = 7.2, 2.4 Hz, 1 H), 4.21–4.11 (m, 2 H), 2.87 (dd, J = 8.0, 2.6 Hz,
1 H), 2.82–2.74 (m, 1 H), 2.68–2.60 (m, 1 H), 2.37 (dd, J = 7.4, 4.0
1H NMR (400 MHz, CDCl3): δ = 9.79 (d, J = 1.2 Hz, 1 H), 7.23 (dd,
J = 5.2, 1.2 Hz, 1 H), 6.97–6.91 (m, 2 H), 5.14 (dd, J = 8.0, 4.0 Hz,
1 H), 4.56 (dd, J = 8.0, 4.0 Hz, 1 H), 4.18–4.12 (m, 2 H), 3.21–3.10
Synthesis 2013, 45, 1612–1623
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
trans-Perhydroindolic Acid as an Organocatalyst
1621
Hz, 2 H), 2.18–2.11 (m, 1 H), 2.06–1.96 (m, 1 H), 1.28–1.24 (m, 3
H), 0.93 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 201.5, 171.3, 92.2, 61.2, 56.4,
H), 2.14 (dd, J = 12.4, 6.2 Hz, 1 H), 2.04–1.94 (m, 1 H), 1.76 (d, J =
11.6 Hz, 3 H), 1.71 – 1.61 (m, 2 H), 1.43–1.33 (m, 1 H), 1.28–1.22
(m, 4 H), 1.21–1.11 (m, 2 H), 1.02–0.93 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 201.5, 171.4, 92.6, 61.2, 54.3,
53.0, 41.5, 34.0, 33.3, 32.4, 27.6, 14.3.
51.9, 41.2, 41.0, 33.9, 31.9, 31.0, 30.9, 26.2, 26.1, 14.3.
HRMS (ESI): m/z [M + Na]+ calcd for C16H25NO5Na: 334.1630;
HRMS (ESI): m/z [M + Na]+ calcd for C14H23NO5Na: 308.1474;
found: 308.1470.
found: 334.1613.
tert-Butyl 2-[(1R,2S,3R,4R)-3-tert-Butyl-4-formyl-2-nitrocyclo-
pentyl]acetate (3pc)
White solid; yield: 30.4 mg (75%); mp 29–30 °C; HPLC (Chiralcel
AS-H, hexane–i-PrOH, 98:2, 210 nm, 0.5 mL·min–1): tR = 16.69
(major), 19.76 min (minor); 91% ee.
tert-Butyl 2-[(1R,2S,3S,4R)-3-Cyclohexyl-4-formyl-2-nitrocy-
clopentyl]acetate (3qc)
Colorless oil; yield: 35.3 mg (80%); HPLC (Chiralcel AD-H,
hexane–i-PrOH, 97:3, 210 nm, 0.4 mL·min–1): tR = 23.56 (major),
29.11 min (minor); 94% ee.
[α]D25 –33.6 (c 0.22, CH2Cl2).
[α]D25 –22.9 (c 0.4, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 9.67 (d, J = 3.2 Hz, 1 H), 5.00 (dd,
J = 7.2, 2.4 Hz, 1 H), 2.86 (dd, J = 8.0, 2.4 Hz, 1 H), 2.81–2.71 (m,
1 H), 2.66–2.56 (m, 1 H), 2.30 (ddd, J = 25.2, 17.2, 7.2 Hz, 2 H),
2.14–2.08 (m, 1 H), 1.99 (td, J = 12.8, 11.0 Hz, 1 H), 1.44 (s, 9 H),
0.93 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 201.6, 170.4, 92.2, 81.6, 56.4,
53.0, 41.7, 35.1, 33.3, 32.4, 28.2, 27.6.
1H NMR (400 MHz, CDCl3): δ = 9.67 (d, J = 2.8 Hz, 1 H), 4.98 (dd,
J = 7.2, 2.4 Hz, 1 H), 2.80 (dd, J = 7.6, 2.4 Hz, 1 H), 2.73–2.64 (m,
2 H), 2.37–2.23 (m, 2 H), 2.14–2.07 (m, 1 H), 2.02–1.95 (m, 1 H),
1.79–1.60 (m, 6 H), 1.44 (s, 9 H), 1.24–1.16 (m, 4 H), 0.99–0.93 (m,
1 H).
13C NMR (100 MHz, CDCl3): δ = 201.6, 170.6, 92.6, 81.6, 54.3,
51.9, 41.2, 35.1, 31.9, 31.0, 30.9, 28.2, 26.2, 26.1.
HRMS (ESI): m/z [M + Na]+ calcd for C18H29NO5Na: 362.1943;
HRMS (ESI): m/z [M + Na]+ calcd for C16H27NO5Na: 336.1787;
found: 336.1781.
found: 362.1942.
Benzyl 2-[(1R,2S,3R,4R)-3-tert-Butyl-4-formyl-2-nitrocyclo-
pentyl]acetate (3pd)
White solid; yield: 33.5 mg (74%); mp 101–102 °C; HPLC (Chiral-
cel AS-H, hexane–i-PrOH, 95:5, 210 nm, 0.4 mL·min–1): tR = 52.63
(minor), 85.50 min (major); 91% ee.
Benzyl 2-[(1R,2S,3S,4R)-3-Cyclohexyl-4-formyl-2-nitrocyclo-
pentyl)acetate (3qd)
White solid; yield: 40.6 mg (84%); mp 57–58 °C; HPLC (Chiralcel
IC-3, hexane–i-PrOH, 95:5, 210 nm, 0.5 mL·min–1): tR = 81.02 (mi-
nor), 101.62 min (major); 95% ee.
[α]D25 –29.2 (c 0.3, CH2Cl2).
[α]D25 –14.5 (c 0.24, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 9.66 (d, J = 3.2 Hz, 1 H), 7.35 (m,
5 H), 5.13 (d, J = 4.0 Hz, 2 H), 4.98 (dd, J = 7.2, 2.4 Hz, 1 H), 2.86
(dd, J = 8.0, 2.4 Hz, 1 H), 2.78–2.76 (m, 1 H), 2.67–2.62 (m, 1 H),
2.45–2.42 (m, 2 H), 2.12 (dd, J = 12.8, 6.4 Hz, 1 H), 2.04–1.98 (m,
1 H), 0.91 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 201.4, 170.2, 135.6, 128.8, 128.6,
128.5, 92.2, 67.0, 56.4, 52.9, 41.5, 34.0, 33.3, 32.4, 27.5.
1H NMR (400 MHz, CDCl3): δ = 9.66 (d, J = 2.8 Hz, 1 H), 7.36–
7.30 (m, 5 H), 5.13 (d, J = 1.6 Hz, 2 H), 4.96 (dd, J = 7.2, 2.4 Hz, 1
H), 2.80 (td, J = 7.6, 2.4 Hz, 1 H), 2.75–2.67 (m, 2 H), 2.43 (dd, J =
7.2, 5.2 Hz, 2 H), 2.17–2.07 (m, 1 H), 2.03–1.92 (m, 1 H), 1.75–1.61
(m, 6 H), 1.40–1.31 (m, 1 H), 1.22–1.12 (m, 2 H), 1.00–0.87 (m, 2
H).
13C NMR (100 MHz, CDCl3): δ = 201.4, 171.2, 135.2, 128.8, 128.6,
128.5, 92.5, 67.0, 54.3, 51.8, 41.2, 41.0, 34.0, 31.9, 31.0, 30.9, 26.2,
26.1.
HRMS (ESI): m/z [M + Na]+ calcd for C19H25NO5Na: 370.1630;
found: 370.1624.
HRMS (ESI): m/z [M + Na]+ calcd for C21H27NO5Na: 396.1787;
found: 396.1779.
Methyl 2-[(1R,2S,3S,4R)-3-Cyclohexyl-4-formyl-2-nitrocyclo-
pentyl]acetate (3qa)
Colorless oil; yield: 32.9 mg (85%); HPLC (Chiralcel IC-3,
hexane–i-PrOH, 95:5, 210 nm, 0.5 mL·min–1): tR = 73.86 (minor),
83.40 min (major); 93% ee.
Ethyl (5R,6R,E)-5-Formyl-7-nitro-6-phenylhept-2-enoate (4)
A similar procedure for the synthesis of 3 was adopted other than
using no additive or only acidic additive to provide major product 4
(35.7 mg, 90%) as a pale yellow oil.
1H NMR (400 MHz, CDCl3): δ = 9.75 (d, J = 2.0 Hz, 1 H), 7.36–
7.30 (m, 3 H), 7.19–7.14 (m, 2 H), 6.75–6.66 (m, 1 H), 5.71 (d, J =
15.6 Hz, 1 H), 4.72 (ddd, J = 22.0, 12.8, 7.2 Hz, 2 H), 4.19–4.15 (m,
2 H), 3.86–3.79 (m, 1 H), 2.98–2.90 (m, 1 H), 2.39–2.31 (m, 2 H),
1.30–1.24 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 201.7, 165.7, 142.8, 136.1 (m),
129.5, 128.7, 128.2, 124.8, 78.2, 60.7, 52.8, 43.2, 30.3, 14.4.
HRMS (ESI): m/z [M + H]+ calcd for C16H20NO5: 306.1355; found:
306.1342.
[α]D25 –21.0 (c 0.6, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 9.66 (d, J = 2.8 Hz, 1 H), 4.96 (dd,
J = 7.2, 2.4 Hz, 1 H), 3.68 (s, 3 H), 3.40–3.33 (m, 1 H), 2.83–2.78
(m, 1 H), 2.76–2.66 (m, 1 H), 2.38 (dd, J = 7.2, 2.4 Hz, 2 H), 2.18–
2.10 (m, 1 H), 2.02–1.92 (m, 1 H), 1.80–1.60 (m, 6 H), 1.40–1.29
(m, 1 H), 1.23–1.10 (m, 2 H), 0.98–0.93 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 201.4, 171.8, 92.5, 54.3, 52.2,
51.8, 41.2, 41.0 (s), 33.7, 31.9, 31.0, 26.2, 26.1.
HRMS (ESI): m/z [M + Na]+ calcd for C15H23NO5Na: 320.1474;
found: 320.1475.
Ethyl 2-[(1R,2S,3S,4R)-3-Cyclohexyl-4-formyl-2-nitrocyclo-
pentyl]acetate (3qb)
Pale yellow oil; yield: 33.2 mg (82%); HPLC (Chiralcel IC-3,
hexane–i-PrOH, 95:5, 210 nm, 0.5 mL·min–1): tR = 58.71 (minor),
61.09 min (major); 99% ee.
(3aR,5R,6R,6aS)-5-(Hydroxymethyl)-6-phenylhexahydrocyclo-
penta[b]pyrrol-2(1H)-one (5)
To the suspension of 3ab (87.3 mg, 0.30 mmol) and NiCl2·6 H2O
(71.3 mg, 0.30 mmol) in MeOH (2 mL) was added NaBH4 (113.6
mg, 10 equiv) under N2 at 0 °C. The mixture was then gradually
warmed to r.t. and stirred for a further 30 min. The mixture was
quenched with sat. NH4Cl soln and extracted with CH2Cl2. The or-
ganic layer was separated and dried (Na2SO4), filtered, and concen-
trated under reduced pressure. The residue was purified by column
[α]D25 –29.1 (c 1.0, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 9.68 (d, J = 2.8 Hz, 1 H), 4.98 (dd,
J = 7.2, 2.4 Hz, 1 H), 4.15 (td, J = 7.2, 1.6 Hz, 2 H), 2.82 (td, J =
7.6, 2.4 Hz, 1 H), 2.77–2.68 (m, 2 H), 2.38 (dd, J = 8.0, 4.0 Hz, 2
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1612–1623

1622
Q. An et al.
FEATURE ARTICLE
chromatography (silica gel) to afford the desired product 5 (59.0
mg, 85%) as a white solid; mp 57–58 °C.
[α]D25 +58.3 (c 0.3, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.30 (dd, J = 10.4, 4.2 Hz, 2 H),
7.22 (dt, J = 4.2, 1.6 Hz, 1 H), 7.18–7.13 (m, 2 H), 3.97 (dd, J = 8.8,
6.4 Hz, 1 H), 3.53 (dd, J = 10.8, 3.6 Hz, 1 H), 3.41–3.34 (m, 1 H),
2.98–2.88 (m, 1 H), 2.61 (ddd, J = 27.6, 14.4, 8.2 Hz, 2 H), 2.33
(ddd, J = 12.6, 7.8, 6.2 Hz, 1 H), 2.27–2.20 (m, 1 H), 2.19–2.12 (m,
1 H).
13C NMR (100 MHz, CDCl3): δ = 177.7, 141.7, 129.1, 127.7, 127.0,
67.7, 63.4, 56.5, 50.1, 37.6, 37.1.
HRMS (ESI): m/z [M + Na]+ calcd for C14H17NO2Na: 254.1153;
found: 254.1157.
2006, 441, 861. (e) Enders, D.; Hüttl, M. R. M.; Runsink, J.;
Raabe, G.; Wendt, B. Angew. Chem. Int. Ed. 2007, 46, 467.
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H.; Milelli, A.; Elsner, P.; Hazell, R. G.; Jørgensen, K. A.
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(4) For selected reviews, see: (a) Comprehensive Asymmetric
Catalysis; Vols. I–III; Jacobsen, E. N.; Pfaltz, A.;
Yamamoto, H., Eds.; Springer: Berlin, 1999. (b) Hayashi, Y.
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Acknowledgment
This work was partly supported by the National Nature Science
Foundation of China (No. 21172143, 21172145 and 21232004),
Science and Technology Commission of Shanghai Municipality
(No. 09JC1407800), Nippon Chemical Industrial Co., Ltd and the
Instrumental Analysis Center of Shanghai Jiao Tong University.
We thank Prof. Tsuneo Imamoto and Dr. Masashi Sugiya for
helpful discussions.
(c) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2000, 122, 4243. (d) Northrup, A. B.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 2458.
(e) Ishihara, K.; Nakano, K. J. Am. Chem. Soc. 2005, 127,
10504. (f) Kano, T.; Tanaka, Y.; Maruoka, K. Org. Lett.
2006, 8, 2687. (g) Hayashi, Y.; Okano, T.; Aratake, S.;
Hazelard, D. Angew. Chem. Int. Ed. 2007, 46, 4922.
(h) Hong, B.-C.; Nimje, R. Y.; Wu, M.-F.; Sadani, A. A.
Eur. J. Org. Chem. 2008, 1449. (i) Baslé, O.; Raimondi, W.;
Sanchez Duque, M. M.; Bonne, D.; Constantieux, T.;
Rodriguez, J. Org. Lett. 2010, 12, 5246. (j) Imashiro, R.;
Uehara, H.; Barbas, C. F. III Org. Lett. 2010, 12, 5250.
(k) Uehara, H.; Imashiro, R.; Hernández-Torres, G.; Barbas,
C. F. III Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 20672.
(l) Tan, B.; Hernandez-Torre, G.; Barbas, C. F. III J. Am.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
nnfomartit
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Synthesis 2013, 45, 1612–1623
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
trans-Perhydroindolic Acid as an Organocatalyst
1623
(10) (a) Zhao, L.; Shen, J.; Liu, D.; Liu, Y.; Zhang, W. Org.
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(11) CCDC 907257 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
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