Highly enantioselective synthesis of biologically important 2,5-dihydropyrroles via phosphoric acid-catalyzed three-component reactions and evaluation of their cytotoxicity

Article abstract of DOI:10.1016/j.tetasy.2011.11.020

A series of new chiral 2,5-dihydropyrrole derivatives were synthesized with high enantioselectivity via phosphoric acid-catalyzed three-component reactions of aldehydes, amino-esters, and alkyl ynones. This approach has the prominent features of high enantioselectivity (up to 98% ee), atom economy, a broad scope of substrate tolerance as well as operational simplicity, leading to a facile and straightforward access to biologically important chiral 2,5-dihydropyrroles. Moreover, the preliminary evaluation on the cytotoxic activity of this type of chiral 2,5-dihydropyrrole derivatives has resulted in the finding of several compounds with effective cytotoxicity to the carcinoma cell line MCF7.

Full text of DOI:10.1016/j.tetasy.2011.11.020

Tetrahedron: Asymmetry 22 (2011) 2056–2064
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Highly enantioselective synthesis of biologically important
2,5-dihydropyrroles via phosphoric acid-catalyzed three-component
reactions and evaluation of their cytotoxicity
Feng Shi a,c, , Zhong-Lin Tao b, Jie Yu b, Shu-Jiang Tu a,c,
⇑
⇑
a College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215000, China
b Department of Chemistry, University of Science and Technology of China, Hefei 230026, China
c School of Chemistry and Chemical Engineering, Xuzhou Normal University, Xuzhou 221116, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 October 2011
Accepted 22 November 2011
A series of new chiral 2,5-dihydropyrrole derivatives were synthesized with high enantioselectivity via
phosphoric acid-catalyzed three-component reactions of aldehydes, amino-esters, and alkyl ynones. This
approach has the prominent features of high enantioselectivity (up to 98% ee), atom economy, a broad
scope of substrate tolerance as well as operational simplicity, leading to a facile and straightforward
access to biologically important chiral 2,5-dihydropyrroles. Moreover, the preliminary evaluation on
the cytotoxic activity of this type of chiral 2,5-dihydropyrrole derivatives has resulted in the finding of
several compounds with effective cytotoxicity to the carcinoma cell line MCF7.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
H
O
HO CH2R
O
i-Pr
R2
R1
O
H3C
The 2,5-dihydropyrrole skeleton not only exists in a number of
natural alkaloids, constituting the core structural element of these
natural products (Fig. 1),1 but also serves as important building
block for a variety of natural products since the double bond of
2,5-dihydropyrroles would allow the introduction of other func-
tional groups.2a–d
More significantly, many 2,5-dihydropyrrole derivatives exhibit
important and versatile bioactivity including antioxidant activity,3
inhibition of the quinone-dependent amine oxidases,4 antimicro-
bial,5 anti-tumor,1c anti-inflammatory,6 and antibiotic7 activities.
As exemplified by those shown in Figure 2, compound I linked with
an acetyl group and its analogues are antioxidants capable of pro-
viding cytoprotection in mammalian cells against oxidative insult
and identifying the structural determinants that are optimal for
protection against individual types of damage.3 Compound II
serves as a tumor inhibitor, which is very active against P388 lym-
phocytic leukemia in vivo.1c Compounds III and IV have anti-
inflammatory6 and antibiotic7 activities, respectively, which are
crucial in the treatment of related diseases.
OH
CH3
O
H
O
HO
H
N
O
N
heliotrine: R1 = H, R2 = OCH3
echinatine: R1 = OH, R2 = H
senecionine: R = H
retrorsine: R = OH
O
R1
O
N
O
N
NR3
Me
O
R2
O
O
N
OMe
mirabimide A: R1 = R3 = Me, R2 = CHMeEt
mirabimide B: R1 = Me, R2 = CHMeEt, R3 = H
mirabimide C: R1 = R3 = Me, R2 = i-Pr
The importance of the 2,5-dihydropyrrole skeleton with regards
to synthetic and medicinal applications has resulted in a demand
for efficient and straightforward syntheses of these compounds,
especially chiral 2,5-dihydropyrrole derivatives. In spite of the
demand, only a few asymmetric transformations have been devel-
mirabimide D: R1 = Ac, R2 = CHMeEt, R3 = Me
Figure 1. Natural products containing the 2,5-dihydropyrrole skeleton.
oped for the construction of these structural skeletons.2c–h One
such method is the aminolysis of optically active vinyl epoxides
⇑
Corresponding authors. Tel./fax: +86 516 83500065.
E-mail address: fshi@xznu.edu.cn (F. Shi).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.11.020

F. Shi et al. / Tetrahedron: Asymmetry 22 (2011) 2056–2064
2057
OCONHCHMe2
OCONHCHMe2
derivatives 4 linked with an acetyl group via a chiral phosphoric
acid (PA)-catalyzed three-component 1,3-dipolar cycloadditions
of aldehydes 1, amino-ester 2, and alkyl ynones 3 (Scheme 1).
O
H3C
Ph
N
H
N
2. Results and discussion
CH3
II
I
Initially, the three-component reaction of 4-nitrobenzaldehyde
1a, diethyl 2-aminomalonate 2, and 2-butyn-3-one 3a in toluene
at room temperature in the presence of 10 mol % of chiral phos-
phoric acid 5 or 6 was employed to screen the most suitable cata-
lyst (Table 1, entries 1–8). The results indicated that catalysts 5d
and 5e with bulky substituents at the 3,30-positions of BINOL-de-
rived phosphoric acids were much more efficient in obtaining the
2,5-dihydropyrrole derivative 4a with high yields and good enanti-
oselectivities (entries 4 and 5). Although the bisphosphoric acid 6
gave the reaction with the highest yield, the enantioselectivity
was unsatisfactory (entry 8). Using phosphoric acid 5e as the best
catalyst, the reaction conditions were further optimized by chang-
ing the solvents (entries 9–12) and molecular sieves (MS) (entries
13 and 14). However, these changes did not improve either the
yield or enantioselectivity in comparison to the results obtained
in toluene with 3 Å MS in the presence of 5e (entry 5). Hence these
reaction conditions, as illustrated by entry 5, were preliminarily re-
garded as the most suitable for other substrates.
Next, aldehyde 1m with an electron-donating group on the aro-
matic ring used in this reaction under the aforementioned reaction
conditions. However the results were disappointing because of
their low yields and moderate ee values (Table 2, entry 1). It is
obvious that the electronic nature of the aldehyde has a significant
influence on this reaction and the reaction conditions should be
further optimized to tolerate various aldehydes with different elec-
tronic properties. As shown in Table 2, the yield and enantioselec-
tivity were considerably improved when increasing the amount of
3a (entry 2) and lowering the reaction temperature from rt to
ꢀ10 °C (entry 3). However, lowering the reaction temperature fur-
ther to ꢀ20 °C caused the ee value to decrease (entry 4). To further
increase the enantioselectivity of this reaction, the loading of cata-
lyst 5e was investigated under ꢀ10 °C and the results revealed that
the ee value of the product 4m had a positive relationship with the
amount of catalyst 5e (entries 3 and 5–8). It is noteworthy that
high enantioselectivity of 84% ee was obtained in the presence of
30 mol % of 5e (entry 8). However at the same time, the yield
was decreased to a moderate level of 50% due to the formation of
a by-product, which was generated by the self-cycloaddition of
two molecules of azomethine ylide produced in situ.11 Neverthe-
less, utilizing different loadings of catalyst according to the elec-
tronic nature of substituents on aldehydes 1 was employed as an
efficient strategy to improve the enantioselectivity under the opti-
mized reaction conditions.
O
O
ArHN
Me
OH
O
OH
Me
(CH2)9
Me
OH
N
O
N
R
Me
R = Me, Et, CMe3
III
IV
Figure 2. Some 2,5-dihydropyrroles exhibiting important bioactivities.
with allyl amine followed by ring-closing metathesis,2c another
method is the tandem Wittig–Horner/intramolecular Michael reac-
tion of optically active hydroxy amide or hydroxy carbamates, fol-
lowed by a retro Diels–Alder cleavage.2d Although these early
approaches accomplished the synthesis of chiral 2,5-dihydropyr-
role derivatives, they employed enantiopure starting materials
and multi-step reactions to construct the optically active 2,5-dihy-
dropyrrole skeletons. Consequently, an enantioselective catalytic
method for the direct construction of the chiral 2,5-dihydropyrrole
skeleton in a one-pot manner is highly desirable with respect to
synthetic efficiency and atom economy.
Recently, phosphoric acid-catalyzed asymmetric multicompo-
nent reactions (MCRs) have emerged as robust tools for the facile
synthesis of highly enantioenriched nitrogenous heterocycles with
structural diversity.8 The strategy of utilizing catalytic asymmetric
1,3-dipolar cycloadditions between azomethine ylides and elec-
tron-deficient alkynes to construct chiral 2,5-dihydropyrrole
skeletons was not established until we reported the first catalytic
asymmetric versions between azomethine ylides and ynones.9
However, that work mainly concentrated on 1,3-dipolar cycloaddi-
tions involving aryl ynones and reported just one alkyl ynone-
involved example. Detailed studies for alkyl ynones have not been
fully described. Furthermore, as shown in Figure 2 and 2,5-
dihydropyrroles I and IV linked with aliphatic acyl groups such
as an acetyl group exhibited significant pharmaceutical activities.
In this regard, the three-component reactions of alkyl ynones as
dipolarophiles with azomethine ylides produced in situ will be
more valuable, since it can lead to the formation of the privileged
2,5-dihydropyrrole skeleton bearing an aliphatic acyl group more
suitable for bioassay. Therefore, based on this anticipation and as
a continuation of our efforts on synthesizing pharmaceutically
relevant heterocycles via MCRs,10 we herein report the highly
enantioselective synthesis of bioactive 2,5-dihydropyrrole
The synthesis of bioactive 2,5-dihydropyrrole derivatives 4
linked with an acetyl group was then carried out by the three-
component reactions of different aldehydes
1 with diethyl
Ar
O
Alkyl
O
OH
O
O
O
CO2Et
P
10-35 mol % PA
CO2Et
CO2Et
+
O
+
H
R
H2N
CO2Et
PhCH3, 3 Å MS
-10°C
Alkyl
R
N
H
Ar
Ar=9-Anthracenyl
PA
1
3
2
4
up to 98% ee
Scheme 1. Enantioselective synthesis of 2,5-dihydropyrroles 4.

2058
F. Shi et al. / Tetrahedron: Asymmetry 22 (2011) 2056–2064
Table 1
Screening of catalysts, solvents, and molecular sievesa
R
5a: R=Ph
5b: R=4-ClPh
5c: R=SiPh3
O
O
P
O
5d: R=9-phenanthrenyl
5e: R=9-anthracenyl
OH
O
O
P
O
P
5f: R=2-naphthyl
O
O
5g: R=2,4,6-(i-Pr)3C6H2
O
O
R
HO
OH
6
CHO
+
O
CO2Et
+
H3C
10 mol % 5 or 6
H2N
CO2Et
O
CO2Et
CO2Et
solvent, rt
CH3
N
H
NO2
O2N
2
1a
3a
4a
Entry
Catalyst
Solvent
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
5a
5b
5c
5d
5e
5f
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
CHCl3
Cl(CH2)2Cl
THF
Toluene
Toluene
59
39
22
72
74
43
36
76
79
76
62
82
71
65
2
3
0
80
94
11
ꢀ11
ꢀ20
13
26
50
5
5g
6
5e
5e
5e
5e
5e
5e
86d
94e
a
b
c
Unless indicated otherwise, the reaction was carried out on a 0.1 mmol scale in a solvent (1 mL) with 3 Å MS (100 mg) for 12 h at rt; the ratio of 1a/2/3a was 1.2:1:2.5.
Isolated yield.
Determined by HPLC.
4 Å MS were used.
5 Å MS were used.
d
e
Table 2
Further optimization of the reaction conditionsa
CHO
+
O
CO2Et
CO2Et
H3C
x mol % 5e
PhCH3, 3 Å MS
T °C
+
H2N
CO2Et
CO2Et
O
CH3
N
OCH3
H
H3CO
1m
2
3a
4m
Entry
T (°C)
x (mol %)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
rt
rt
10
10
10
10
15
20
25
30
32
71
70
80
88
82
56
50
50d
57e
61
54
70
74
79
84
ꢀ10
ꢀ20
ꢀ10
ꢀ10
ꢀ10
ꢀ10
a
b
c
Unless indicated otherwise, the reaction was carried out on a 0.1 mmol scale in toluene (1 mL) with 3 Å MS (100 mg) for 30 h; the ratio of 1m/2/3a was 1.2:1:5.
Isolated yield.
Determined by HPLC.
The ratio of 1m/2/3a was 1.2:1:2.5, and the reaction time was 12 h.
The ratio of 1m/2/3a was 1.2:1:5, and the reaction time was 12 h.
d
e

F. Shi et al. / Tetrahedron: Asymmetry 22 (2011) 2056–2064
2059
Table 3
The synthesis of bioactive 2,5-dihydropyrrole derivatives 4a
O
H3C
O
CO2Et
CO2Et
x mol % 5e
CO2Et
CO2Et
+
+
R
H
H2N
PhCH3, 3 Å MS
-10 oC
O
CH3
R
N
H
1
2
3a
4
Entry
4
R
x (mol %)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
4-FC6H4
4-BrC6H4
4-CNC6H4
2-BrC6H4
4-MsC6H4
Ph
2-Naphthyl
3,4-Cl2C6H3
4-MeC6H4
4-MeOC6H4
3-MeOC6H4
10
10
10
10
10
10
20
20
20
20
20
35
30
35
35
35
30
30
73
88
87
97
74
71
62
54
81
64
68
47
50
36
62
50
24
31
98
92
90
78
82
94
86
97
79
84
93
83
84
85
74
61
86d
66e
2-Thiophenyl
2-Furanyl
4-MeOC6H4CH@CH
Cyclohexanyl
a
b
c
Unless indicated otherwise, the reaction was carried on a 0.1 mmol scale in toluene (1 mL) with 3 Å MS (100 mg) at ꢀ10 °C for 30 h; the ratio of 1/2/3a was 1.2:1:5.
Isolated yield.
Determined by HPLC.
The reaction time was 48 h.
The reaction time was 72 h.
d
e
2-aminomalonate 2 and 2-butyn-3-one 3a under the optimal
reaction conditions, combined with the strategy of employing
different loadings of the catalyst on the basis of the electronic nat-
ure of aldehydes 1. Only 10 mol % of catalyst 5e was needed for
aromatic aldehydes with strong electron-withdrawing groups (Ta-
ble 3, entries 1–6), while 20 mol % of 5e was loaded for those with
electronically neutral groups (entries 9 and 10) as well as some
aldehydes bearing electron-withdrawing groups (entries 7, 8, and
11). For aromatic aldehydes with electron-donating groups (entries
12–14), hetero-aromatic aldehydes (entries 15 and 16) and ali-
phatic aldehydes (entries 17 and 18), 30–35 mol % of 5e was uti-
lized to enhance the enantioselectivity of the reaction. It is
obvious that this approach can be applied to various aromatic, het-
ero-aromatic, and aliphatic aldehydes, leading to the efficient syn-
thesis of bioactive 2,5-dihydropyrrole derivatives 4 linked with an
acetyl group in high to excellent enantioselectivity (up to 98% ee).
Furthermore, the substrate scope with respect to alkyl ynones 3
was also explored by the reactions of 4-nitrobenzaldehyde 1a, and
2-aminomalonate 2 with a variety of aliphatic ynones 3 bearing
linear, branched, cyclic alkyl groups or benzyl group in the pres-
ence of 10 mol % of catalyst 5e under the optimized reaction con-
ditions (Table 4). Linear alkyl ynones or benzyl ynones gave
higher stereoselectivities than branched and cyclic alkyl ynones
(entries 1–3, 6 vs 4, and 5). In general, this protocol is amenable
to a wide scope of aliphatic ynones with different types of alkyl
and benzyl groups in good enantioselectivities (87–98% ee).
The structures of the synthesized 2,5-dihydropyrroles deriva-
tives 4 were unambiguously characterized by IR, 1H, 13C NMR,
and HRMS (ESI). The absolute configuration of compound 4a was
determined to be (5S) by comparing its specific rotation
In order to evaluate the possible cytotoxicity of these chiral
heterocyclic compounds, the IC50 values of some selected 2,5-
dihydropyrroles 4 to mammary carcinoma cell line MCF7 were
tested (Table 5). All of the compounds tested exhibited moderate
cytotoxicity to MCF7 cells. Compounds 4a, 4c, and 4l (entries 1, 2,
4, and 6) showed much stronger cytotoxicity than the other com-
pounds. It is noteworthy that the IC50 value of compounds 4a
with 94% ee is lower than that of 4a with 86% ee (entry 1 vs
2), which indicates that the cytotoxicity of the (S)-enantiomer
of 4a should be stronger than its racemic counterpart and the
(R)-enantiomer. Although the cytotoxicity to MCF7 cells of the
tested compounds 4 was moderate, it should be noted that high
cytotoxicity is not a prerequisite for the further development of
a compound as an anticancer drug candidate.12 Therefore, those
2,5-dihydropyrroles 4 with a moderate cytotoxicity could still
be promising antitumor drug candidates after further structural
modification and biological investigations.
3. Conclusions
In conclusion, we have achieved the highly enantioselective
synthesis of new bioactive 2,5-dihydropyrrole derivatives linked
with an aliphatic acyl group via chiral phosphoric acid-catalyzed
three-component 1,3-dipolar cycloadditions of aldehydes, amino-
esters, and alkyl ynones. This approach has the prominent features
of high enantioselectivity (up to 98% ee), atom economy, and a
broad scope of substrate tolerance as well as operational simplic-
ity, leading to a facile and straightforward access to biologically
important chiral 2,5-dihydropyrrole derivatives. Moreover, the
preliminary evaluation of the cytotoxic activity of this type of
2,5-dihydropyrrole derivative has resulted in us finding several
compounds with promising antitumor activity. Therefore, this
½
a 2D0
ꢁ
¼ þ178:4 (c 0.5, CHCl3) to the literature value ½a D20
¼ þ173:4
ꢁ
(c 0.5, CHCl3).9 The configurations of the other new 2,5-dihydro-
pyrroles 4 were assigned by analogy.

2060
F. Shi et al. / Tetrahedron: Asymmetry 22 (2011) 2056–2064
Table 4
The scope of the alkyl ynonesa
O
O
CO2Et
Alkyl
5e
10 mol % , -10°C
+
H
+
H2N
CO2Et
CO2Et
CO2Et
PhCH3, 3 Å MS
O
Alkyl
O2N
N
H
3
2
1a
O2N
4
Entry
1
4
3
Yieldb (%)
eec (%)
98
O
H3C
4a
4s
73
3a
O
2
3
4
5
67
74
50
69
51
97
95
87
94
97
H3C (CH2)7
3b
O
Ph
4t
3c
O
Et
4u
4v
4w
3d
Et
O
3e
O
3f
6
Bn
a
Unless indicated otherwise, the reaction was carried on a 0.1 mmol scale in toluene (1 mL) with 3 Å MS (100 mg) at ꢀ10 °C for 30 h; the ratio of 1a/2/3 was 1.2:1:5.
b
c
Isolated yield.
Determined by HPLC.
protocol not only allows the rapid construction of the chiral 2,5-
dihydropyrrole architecture, which has potential application in
synthetic and medicinal chemistry, but also provides enantioen-
riched 2,5-dihydropyrrole derivatives linked with an aliphatic acyl
group for further structural modification and bioassay.
4. Experimental
4.1. General information
Table 5
The cytotoxicity of 2,5-dihydropyrroles 4 to MCF7 cellsa
NMR spectra were recorded on a Brucker-400 MHz spectrome-
ter. HRMS (Bio TOF Q) spectra were recorded on P-SIMS-Gly of Bru-
ker Daltonics Inc. Infrared spectra were recorded on a Nicolet MX-
1E FT-IR spectrometer. HPLC analysis was performed on Waters-
Breeze (2487 Dual Absorbance Detector and 1525 Binary HPLC
Pump) and Agilent 1200. Chiralpak OD, IC, IA columns were pur-
chased from Daicel Chemical Industries, LTD.
O
CO2Et
CO2Et
N
R
H
4
Analytical grade solvents for column chromatography and com-
mercially available reagents were used as received. Toluene was
dried over Na and distilled prior to use. All starting materials were
commercially available and used directly. Substrates 3b–3f were
obtained according to the literature methods.9,13 Catalysts 5a–5g
and 6 were prepared according to the previously described prece-
dures14 and 5e was acidified with 4 M HCl before use.
a
Entry
4
R
IC50 (lg/mL)
1
2
3
4
5
6
7
8
4a (94% ee)
4a (86% ee)
4b
4c
4f
4l
4o
4q
4-NO2C6H4
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
4-CNC6H4
4-MeC6H4
2-Thiophenyl
4-MeOC6H4CH@CH
166.92
201.40
2161.89
810.93
1378.78
617.45
1360.20
1698.66
4-Ethylhex-1-yn-3-one 3d: colorless liquid; 1H NMR (CDCl3,
400 MHz) d (ppm): 3.20 (s, 1H, CH), 2.39–2.35 (m, 1H, CH), 1.80–
1.70 (m, 2H, CH2), 1.64–1.53 (m, 2H, CH2), 0.91 (t, J = 7.2 Hz, 6H,
2CH3); 13C NMR (CDCl3, 100 MHz) d (ppm): 191.5, 78.6, 77.3,
77.0, 16.7, 57.5, 23.7, 11.5.
a
The IC50 value corresponded to the compound concentration causing 50%
mortality in MCF7 cells.

F. Shi et al. / Tetrahedron: Asymmetry 22 (2011) 2056–2064
2061
4.2. General procedure for the asymmetric synthesis of 2,5-
dihydropyrroles 4a–4w
3362, 3082, 2961, 2927, 1732, 1682, 1529, 1465, 1355, 1282,
1229, 1119, 1074, 1040, 852, 743, 602; ESI FTMS exact mass calcd
for (C18H20N2O7+H)+ requires m/z 377.1349, found m/z 377.1329;
enantiomeric excess: 90%, determined by HPLC (Daicel Chirapak
OD-H, hexane–2-propanol = 70:30, flow rate 1.0 mL/min,
T = 30 °C, 254 nm): tR = 5.97 min (minor), tR = 9.25 min (major).
Unless indicated otherwise, a solutionof aldehyde 1 (0.12 mmol),
amino-ester 2 (0.1 mmol), catalyst 5e (0.01–0.035 mmol), and
3 Å molecular sieves (100 mg) in toluene (1 mL) was stirred and
cooled to ꢀ10 °C. Then, ynone 3 (0.5 mmol) was added to the solu-
tion. After the reaction mixture was stirred at ꢀ10 °C for 30 h, it
was filtered to remove the molecular sieves and the solid powder
was washed with ethyl acetate. The resulting solution was quenched
with saturated aqueous NaHCO3 and the aqueous layer was ex-
tracted with ethyl acetate. The combined organic layers were dried
over anhydrous Na2SO4. After evaporation under the reduced pres-
sure, the residue was purified by flash column chromatography on
silica gel to yield pure products 4a–4w.
4.3.4. (5S)-Diethyl 4-acetyl-5-(4-fluorophenyl)-1H-pyrrole-
2,2(5H)-dicarboxylate 4d
Flash column chromatography eluent, petroleum ether–ethyl
acetate = 8:1; yield: 97%; colorless oil;
½
a 2D0
ꢁ
¼ þ170:4 (c 0.2,
CHCl3); 1H NMR (CDCl3, 400 MHz) d (ppm): 7.27–7.24 (m, 2H,
ArH), 6.97 (dt, J1 = 8.8 Hz, J2 = 2.0 Hz, 2H, ArH), 6.76 (d, J = 2.0 Hz,
1H, @CH), 5.39 (d, J = 2.0 Hz, 1H, CH), 4.33–4.26 (m, 4H, 2CH2),
3.43 (s, 1H, NH), 2.27 (s, 3H, CH3), 1.31 (dt, J1
= 7.2 Hz,
J2 = 1.6 Hz, 6H, 2CH3); 13C NMR (CDCl3, 100 MHz) d (ppm): 194.2,
169.4, 169.2, 163.5, 161.1, 147.9, 137.6, 137.6, 135.3, 129.3,
129.3, 115.4, 115.2, 79.0, 67.4, 62.7, 62.6, 27.8, 14.0, 14.0; IR
4.3. Characterization of compounds 4
4.3.1. (5S)-Diethyl 4-acetyl-5-(4-nitrophenyl)-1H-pyrrole-
2,2(5H)-dicarboxylate 4a
(KBr): m 3358, 3074, 2961, 2931, 1732, 1628, 1605, 1510, 1367,
1281, 1224, 1119, 1038, 838, 747; ESI FTMS exact mass calcd for
(C18H20FNO5+H)+ requires m/z 350.1404, found m/z 350.1411;
enantiomeric excess: 78%, determined by HPLC (Daicel Chirapak
OD-H, hexane–2-propanol = 90:10, flow rate 1.0 mL/min,
T = 30 °C, 254 nm): tR = 6.01 min (major), tR = 7.08 min (minor).
Flash column chromatography eluent, petroleum ether–ethyl
acetate = 8:1; yield: 73%; yellow solid; mp 125–126 °C;
½
a 2D0
ꢁ
¼ þ178:4 (c 0.5, CHCl3); 1H NMR (CDCl3, 400 MHz) d (ppm):
8.14 (d, J = 8.8 Hz, 2H, ArH), 7.51 (d, J = 8.8 Hz, 2H, ArH), 6.81 (d,
J = 2.0 Hz, 1H, @CH), 5.51 (s, 1H, CH), 4.37–4.25 (m, 4H, 2CH2),
3.61 (s, 1H, NH), 2.31 (s, 1H, CH3), 1.33 (t, J = 7.2 Hz, 6H, 2CH3);
13C NMR (CDCl3, 100 MHz) d (ppm): 193.9, 169.1, 169.0, 149.3,
147.4, 147.3, 136.1, 128.8, 123.6, 79.3, 67.2, 63.0, 62.7, 27.6, 14.1;
4.3.5. (5S)-Diethyl 4-acetyl-5-(4-bromophenyl)-1H-pyrrole-
2,2(5H)-dicarboxylate 4e
Flash column chromatography eluent, petroleum ether–ethyl
IR (KBr):
m
3355, 3081, 2963, 2924, 1732, 1682, 1518, 1348,
acetate = 8:1; yield: 74%; colorless oil;
½
a 2D0
ꢁ
¼ þ158:1 (c 0.5,
1283, 1228, 1110, 1039, 854, 704, 593; ESI FTMS exact mass calcd
for (C18H20N2O7+H)+ requires m/z 377.1349, found m/z 377.1365;
enantiomeric excess: 98%, determined by HPLC (Daicel Chirapak
OD-H, hexane–2-propanol = 70:30, flow rate 1.0 mL/min,
T = 30 °C, 254 nm): tR = 5.80 min (major), tR = 7.69 min (minor).
CHCl3); 1H NMR (CDCl3, 400 MHz) d (ppm): 7.41 (d, J = 8.4 Hz,
2H, ArH), 7.17 (d, J = 8.4 Hz, 2H, ArH), 6.76 (d, J = 2.0 Hz, 1H,
@CH), 5.36 (s, 1H, CH), 4.33–4.26 (m, 4H, 2CH2), 3.45 (s, 1H, NH),
2.27 (s, 3H, CH3), 1.31(dt, J1 = 7.2 Hz, J2 = 1.2 Hz, 6H, 2CH3); 13C
NMR (CDCl3, 100 MHz) d (ppm): 194.1, 169.3, 169.1, 147.7, 140.9,
135.5, 131.5, 129.4, 121.7, 79.1, 67.5, 62.7, 62.6, 27.8, 14.0, 14.0;
4.3.2. (5S)-Diethyl 4-acetyl-5-(3-nitrophenyl)-1H-pyrrole-
2,2(5H)-dicarboxylate 4b
IR (KBr): m 3357, 3088, 2981, 2922, 1735, 1683, 1366, 1274,
1231, 1109, 1011, 857; ESI FTMS exact mass calcd for
(C18H20BrNO5+H)+ requires m/z 410.0603, found m/z 410.0611;
enantiomeric excess: 82%, determined by HPLC (Daicel Chirapak
OD-H, hexane–2-propanol = 90:10, flow rate 1.0 mL/min,
T = 30 °C, 254 nm): tR = 6.34 min (major), tR = 7.97 min (minor).
Flash column chromatography eluent, petroleum ether–ethyl
acetate = 6:1); yield: 88%; colorless oil; ½a D20
¼ þ249:2 (c 0.3,
ꢁ
CHCl3); 1H NMR (CDCl3, 400 MHz) d (ppm): 8.21 (t, J = 8.0 Hz, 1H,
ArH), 8.10–8.07 (m, 1H, ArH), 7.69 (d, J = 7.6 Hz, 1H, ArH), 7.45 (t,
J = 8.0 Hz, 1H, ArH), 6.82 (d, J = 2.0 Hz, 1H, @CH), 5.52 (d,
J = 1.6 Hz, 1H, CH), 4.38–4.26 (m, 4H, 2CH2), 3.64 (s, 1H, NH),
2.32 (s, 3H, CH3), 1.34 (q, J = 7.2 Hz, 6H, 2CH3); 13C NMR (CDCl3,
100 MHz) d (ppm): 194.0, 169.1, 169.0, 148.4, 147.2, 144.4,
136.3, 134.3, 129.1, 122.8, 122.7, 79.2, 67.1, 63.0, 62.8, 27.6, 14.1,
4.3.6. (5S)-Diethyl 4-acetyl-5-(4-cyanophenyl)-1H-pyrrole-
2,2(5H)-dicarboxylate 4f
Flash column chromatography eluent, petroleum ether–ethyl
acetate = 6:1; yield: 71%; pale yellow solid; ½a D20
¼ þ215:0 (c 0.3,
ꢁ
14.0; IR (KBr):
m
3360, 3089, 2923, 2851, 1731, 1680, 1530, 1460,
CHCl3); mp 90–92 °C; 1H NMR (CDCl3, 400 MHz) d (ppm): 7.57
(d, J = 8.4 Hz, 2H, ArH), 7.44 (d, J = 8.4 Hz, 2H, ArH), 6.79 (d,
J = 2.0 Hz, 1H, @CH), 5.45 (d, J = 2.0 Hz, 1H, CH), 4.36–4.24 (m,
4H, 2CH2), 3.58 (s, 1H, NH), 2.30 (s, 3H, CH3), 1.32 (t, J = 7.2 Hz,
6H, 2CH3); 13C NMR (CDCl3, 100 MHz) d (ppm): 194.0, 169.1,
169.0, 147.3, 147.3, 136.0, 132.2, 128.6, 118.9, 111.5, 79.2, 67.5,
1348, 1224, 1111, 1040, 856, 738, 699, 602; ESI FTMS exact mass
calcd for (C18H20N2O7+H)+ requires m/z 377.1349, found m/z
377.1356; enantiomeric excess: 92%, determined by HPLC (Daicel
Chirapak OD-H, hexane–2-propanol = 70:30, flow rate 1.0 mL/
min, T = 30 °C, 254 nm): tR = 5.64 min (major), tR = 6.56 min
(minor).
62.9, 62.6, 27.6, 14.1, 14.0; IR (KBr):
m 3356, 3090, 2982, 2922,
2227, 1735, 1681, 1368, 1278, 1232, 1111, 1038, 855, 565; ESI
FTMS exact mass calcd for (C19H20N2O5+H)+ requires m/z
357.1451, found m/z 357.1458; enantiomeric excess: 94%, deter-
mined by HPLC (Daicel Chirapak OD-H, hexane–2-propa-
4.3.3. (5S)-Diethyl 4-acetyl-5-(2-nitrophenyl)-1H-pyrrole-
2,2(5H)-dicarboxylate 4c
Flash column chromatography eluent, petroleum ether–ethyl
acetate = 6:1; yield: 87%; yellow oil; ½a D20
ꢁ
¼ þ364:4 (c 0.4, CHCl3);
nol = 90:10,
flow
rate
1.0 mL/min,
T = 30 °C,
254 nm):
1H NMR (CDCl3, 400 MHz)
d (ppm): 7.83 (dd, J1 = 8.0 Hz,
tR = 11.36 min (major), tR = 16.13 min (minor).
J2 = 1.2 Hz, 1H, ArH), 7.50 (dt, J1 = 8.2 Hz, J2 = 1.2 Hz, 1H, ArH),
7.39–7.33 (m, 2H, ArH), 6.85 (d, J = 2.0 Hz, 1H, @CH), 6.08 (dd,
J1 = 6.4 Hz, J2 = 2.0 Hz, 1H, CH), 4.38–4.20 (m, 4H, 2CH2), 3.91 (d,
J = 6.4 Hz, 1H, NH), 2.31 (s, 3H, CH3), 1.33 (t, J = 7.2 Hz, 3H, CH3),
1.29 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (CDCl3, 100 MHz) d (ppm):
193.8, 169.0, 168.9, 149.4, 146.9, 136.8, 136.7, 132.9, 129.4,
4.3.7. (5S)-Diethyl 4-acetyl-5-(2-bromophenyl)-1H-pyrrole-
2,2(5H)-dicarboxylate 4g
Flash column chromatography eluent, petroleum ether–ethyl
acetate = 8:1; yield: 62%; colorless oil;
½
a 2D0
ꢁ
¼ þ117:4 (c 0.2,
CHCl3); 1H NMR (CDCl3, 400 MHz) d (ppm): 7.48–7.45 (m, 1H,
ArH), 7.15 (dt, J1 = 7.2 Hz, J2 = 1.2 Hz, 1H, ArH), 7.03–6.99 (m, 2H,
128.2, 124.2, 79.0, 63.0, 62.4, 62.0, 27.3, 14.1, 14.0; IR (KBr):
m

2062
F. Shi et al. / Tetrahedron: Asymmetry 22 (2011) 2056–2064
ArH), 6.80 (d, J = 2.0 Hz, 1H, @CH), 5.84 (d, J = 2.0 Hz, 1H, CH), 4.25–
4.15 (m, 4H, 2CH2), 3.53 (s, 1H, NH), 2.22 (s, 3H, CH3), 1.25 (t,
J = 7.2 Hz, 3H, CH3), 1.19 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (CDCl3,
100 MHz) d (ppm): 192.8, 168.2, 146.4, 139.9, 135.4, 131.9,
129.9, 128.1, 126.8, 123.2, 77.9, 65.5, 61.8, 61.4, 28.7, 13.0, 12.9;
4.3.11. (5S)-Diethyl 4-acetyl-5-(3,4-dichlorophenyl)-1H-pyrrole-
2,2(5H)-dicarboxylate 4k
Flash column chromatography eluent, petroleum ether–ethyl
acetate = 8:1; yield: 68%; colorless oil;
½
a 2D0
ꢁ
¼ þ126:1 (c 0.2,
CHCl3); 1H NMR (CDCl3, 400 MHz) d (ppm): 7.41 (d, J = 2.0 Hz,
1H, ArH), 7.34 (d, J = 8.4 Hz, 1H, ArH), 7.16 (dd, J1 = 8.4 Hz,
J2 = 2.0 Hz, 1H, ArH), 6.77 (d, J = 1.6 Hz, 1H, @CH), 5.36 (d,
J = 1.6 Hz, 1H, CH), 4.35–4.24 (m, 4H, 2CH2), 3.52 (s, 1H, NH),
2.30 (s, 3H, CH3), 1.32 (q, J = 6.8 Hz, 6H, 2CH3); 13C NMR (CDCl3,
100 MHz) d (ppm): 194.0, 169.2, 169.0, 147.4, 142.3, 135.8,
132.4, 131.6, 130.2, 129.7, 127.3, 79.1, 66.9, 62.9, 62.7, 27.7, 14.0;
IR (KBr):
m 3352, 3062, 2983, 2928, 1735, 1628, 1470, 1367,
1278, 1231, 1108, 1026, 856, 751; ESI FTMS exact mass calcd for
(C18H20BrNO5+H)+ requires m/z 410.0603, found m/z 410.0593;
enantiomeric excess: 86%, determined by HPLC (Daicel Chirapak
OD-H, hexane–2-propanol = 95:5, flow rate 1.0 mL/min, T = 30 °C,
254 nm): tR = 10.45 min (minor), tR = 11.23 min (major).
IR (KBr):
m 3357, 3090, 2983, 2937, 1737, 1682, 1466, 1367,
1277, 1235, 1111, 1032, 858, 674, 852; ESI FTMS exact mass calcd
for (C18H19Cl2NO5+H)+ requires m/z 399.0640, found m/z 399.0640;
enantiomeric excess: 93%, determined by HPLC (Daicel Chirapak
OD-H, hexane–2-propanol = 90:10, flow rate 1.0 mL/min, T =
30 °C, 254 nm): tR = 6.29 min (major), tR = 8.18 min (minor).
4.3.8. (5S)-Diethyl 4-acetyl-5-(4-(methylsulfonyl)phenyl)-1H-
pyrrole-2,2(5H)-dicarboxylate 4h
Flash column chromatography eluent, petroleum ether–ethyl
acetate = 3:1; yield: 54%; colorless oil;
½
a 2D0
ꢁ
¼ þ181:4 (c 0.3,
CHCl3); 1H NMR (CDCl3, 400 MHz) d (ppm): 7.86 (d, J = 8.4 Hz,
2H, ArH), 7.53 (d, J = 8.4 Hz, 2H, ArH), 6.80 (d, J = 2.0 Hz, 1H,
@CH), 5.49 (s, 1H, CH), 4.38–4.25 (m, 4H, 2CH2), 3.60 (s, 1H, NH),
3.02 (s, 3H, CH3), 2.31 (s, 3H, CH3), 1.32 (t, J = 7.2 Hz, 6H, 2CH3);
13C NMR (CDCl3, 100 MHz) d (ppm): 194.0, 169.1, 168.9, 148.3,
147.4, 139.6, 136.1, 128.9, 127.5, 79.3, 67.3, 63.0, 62.6, 44.5, 27.6,
4.3.12. (5S)-Diethyl 4-acetyl-5-p-tolyl-1H-pyrrole-2,2(5H)-
dicarboxylate 4l
Flash column chromatography eluent, petroleum ether–ethyl
acetate = 8:1; yield: 47%; colorless oil;
½
a 2D0
ꢁ
¼ þ135:1 (c 0.4,
CHCl3); 1H NMR (CDCl3, 400 MHz) d (ppm): 7.15 (d, J = 8.0 Hz,
2H, ArH), 7.10 (d, J = 8.0 Hz, 2H, ArH), 6.77 (d, J = 2.0 Hz, 1H,
@CH), 5.35 (d, J = 2.0 Hz, 1H, CH), 4.33–4.24 (m, 4H, 2CH2), 3.37
(s, 1H, NH), 2.30 (s, 3H, CH3), 2.25 (s, 3H, CH3), 1.30 (dt,
J1 = 7.2 Hz, J2 = 2.0 Hz, 6H, 2CH3); 13C NMR (CDCl3, 100 MHz) d
(ppm): 194.4, 169.5, 169.2, 148.0, 138.7, 137.5, 135.2, 129.2,
14.0; IR (KBr):
m 3354, 3088, 2983, 2929, 1732, 1679, 1410, 1370,
1305, 1228, 1148, 1038, 957, 855, 769, 545; ESI FTMS exact mass
calcd for (C19H23NO7S+H)+ requires m/z 410.1273, found m/z
410.1248; enantiomeric excess: 97%, determined by HPLC (Daicel
Chirapak OD-H, hexane–2-propanol = 70:30, flow rate 1.0 mL/
min, T = 30 °C, 254 nm): tR = 10.83 min (major), tR = 12.38 min
(minor).
127.5, 79.1, 68.0, 62.6, 62.5, 28.0, 21.1, 14.0; IR (KBr):
m 3356,
3091, 2981, 2924, 1735, 1683, 1367, 1271, 1230, 1110, 1033,
856, 820, 599, 544; ESI FTMS exact mass calcd for (C19H23NO5+H)+
requires m/z 346.1654, found m/z 346.1649; enantiomeric excess:
83%, determined by HPLC (Daicel Chirapak OD-H, hexane–2-propa-
nol = 95:5, flow rate 1.0 mL/min, T = 30 °C, 254 nm): tR = 7.99 min
(major), tR = 9.17 min (minor).
4.3.9. (5S)-Diethyl 4-acetyl-5-phenyl-1H-pyrrole-2,2(5H)-
dicarboxylate 4i
Flash column chromatography eluent, petroleum ether–ethyl
acetate = 8:1; yield: 81%; colorless oil;
½
a 2D0
ꢁ
¼ þ122:2 (c 0.1,
CHCl3); 1H NMR (CDCl3, 400 MHz) d (ppm): 7.31–7.23 (m, 5H,
ArH), 6.78 (d, J = 2.0 Hz, 1H, @CH), 5.39 (d, J = 1.6 Hz, 1H, CH),
4.33–4.24 (m, 4H, 2CH2), 3.41 (s, 1H, NH), 2.26 (s, 3H, CH3), 1.31
(dt, J1 = 7.2 Hz, J2 = 0.4 Hz, 6H, 2CH3); 13C NMR (CDCl3, 100 MHz)
d (ppm): 194.3, 169.5, 169.2, 148.0, 141.7, 135.3, 128.5, 127.8,
4.3.13. (5S)-Diethyl 4-acetyl-5-(4-methoxyphenyl)-1H-pyrrole-
2,2(5H)-dicarboxylate 4m
Flash column chromatography eluent, petroleum ether–ethyl
acetate = 6:1; yield: 50%; colorless oil;
½
a 2D0
ꢁ
¼ þ147:8 (c 0.4,
CHCl3); 1H NMR (CDCl3, 400 MHz) d (ppm): 7.18 (d, J = 8.8 Hz,
2H, ArH), 6.82 (d, J = 8.8 Hz, 2H, ArH), 6.75 (d, J = 2.0 Hz, 1H,
@CH), 5.35 (d, J = 2.0 Hz, 1H, CH), 4.33–4.24 (m, 4H, 2CH2), 3.77
(s, 3H, OCH3), 3.35 (s, 1H, NH), 2.25 (s, 3H, CH3), 1.30 (dt,
J1 = 7.2 Hz, J2 = 3.2 Hz, 6H, 2CH3); 13C NMR (CDCl3, 100 MHz) d
(ppm): 194.4, 169.5, 169.2, 159.2, 148.0, 135.0, 133.8, 128.7,
127.6, 79.2, 68.3, 62.6, 62.5, 27.9, 14.0, 14.0; IR (KBr):
m 3356,
3062, 2981, 2928, 1731, 1682, 1456, 1367, 1229, 1111, 1030,
857, 700; ESI FTMS exact mass calcd for (C18H21NO5+H)+ requires
m/z 332.1498, found m/z 332.1485; enantiomeric excess: 79%,
determined by HPLC (Daicel Chirapak OD-H, hexane–2-propa-
nol = 95:5, flow rate 0.5 mL/min, T = 30 °C, 254 nm): tR = 17.80 min
(major), tR = 19.56 min (minor).
113.9, 79.0, 67.7, 62.6, 62.5, 55.2, 28.0, 14.0; IR (KBr):
m 3355,
3078, 2963, 2924, 2852, 1735, 1679, 1609, 1513, 1463, 1366,
1231, 1174, 1109, 1031, 834; ESI FTMS exact mass calcd for
(C19H23NO6)+ requires m/z 361.1525, found m/z 361.1503; enantio-
meric excess: 84%, determined by HPLC (Daicel Chirapak OD-H,
hexane–2-propanol = 95:5, flow rate 1.0 mL/min, T = 30 °C,
254 nm): tR = 13.12 min (major), tR = 15.20 min (minor).
4.3.10. (5S)-Diethyl 4-acetyl-5-(naphthalen-2-yl)-1H-pyrrole-
2,2(5H)-dicarboxylate 4j
Flash column chromatography eluent, petroleum ether–ethyl
acetate = 9:1; yield: 64%; colorless oil;
½
a 2D0
ꢁ
¼ þ150:0 (c 0.1,
CHCl3); 1H NMR (CDCl3, 400 MHz) d (ppm): 7.81–7.76 (m, 4H,
ArH), 7.47–7.41 (m, 2H, ArH), 7.36 (dd, J1 = 8.4 Hz, J2 = 1.6 Hz, 1H,
ArH), 6.83 (d, J = 2.0 Hz, 1H, @CH), 5.57 (d, J = 2.0 Hz, 1H, CH),
4.36–4.26 (m, 4H, 2CH2), 3.51 (s, 1H, NH), 2.26 (s, 3H, CH3), 1.32
(dt, J1 = 7.2 Hz, J2 = 0.8 Hz, 6H, 2CH3); 13C NMR (CDCl3, 100 MHz)
d (ppm): 194.3, 169.5, 169.2, 147.9, 138.9, 135.4, 133.3, 133.1,
128.4, 128.1, 127.6, 127.0, 126.0, 125.9, 125.2, 79.2, 68.3, 62.7,
4.3.14. (5S)-Diethyl 4-acetyl-5-(3-methoxyphenyl)-1H-pyrrole-
2,2(5H)-dicarboxylate 4n
Flash column chromatography eluent, petroleum ether–ethyl
acetate = 7:1; yield: 36%; colorless oil;
½
a 2D0
ꢁ
¼ þ189:8 (c 0.1,
CHCl3); 1H NMR (CDCl3, 400 MHz) d (ppm): 7.20 (t, J = 8.0 Hz, 1H,
ArH), 6.87–6.82 (m, 2H, ArH), 6.80–6.75 (m, 2H, ArH, and @CH),
5.36 (d, J = 1.6 Hz, 1H, CH), 4.33–4.24 (m, 4H, 2CH2), 3.77 (s, 3H,
OCH3), 3.40 (s, 1H, NH), 2.26 (s, 3H, CH3), 1.30 (t, J = 7.2 Hz, 6H,
2CH3); 13C NMR (CDCl3, 100 MHz) d (ppm): 194.3, 169.5, 169.1,
159.8, 147.9, 143.2, 135.3, 129.5, 120.0, 113.4, 113.2, 79.2, 68.2,
62.6, 27.9, 14.1; IR (KBr):
m 3361, 3055, 2981, 2927, 1734, 1681,
1367, 1273, 1230, 1190, 1036, 856, 820, 755, 479; ESI FTMS exact
mass calcd for (C22H23NO5+H)+ requires m/z 382.1655, found m/z
382.1640; enantiomeric excess: 84%, determined by HPLC (Daicel
Chirapak IC-H, hexane–2-propanol = 90:10, flow rate 1.0 mL/min,
T = 30 °C, 254 nm): tR = 28.36 min (minor), tR = 30.34 min (major).
62.6, 62.5, 55.2, 27.9, 14.0, 14.0; IR (KBr):
m 3355, 3085, 2961,
2921, 1737, 1682, 1601, 1466, 1367, 1277, 1231, 1159, 1041,

F. Shi et al. / Tetrahedron: Asymmetry 22 (2011) 2056–2064
2063
858, 765, 701, 596; ESI FTMS exact mass calcd for (C19H23NO6)+ re-
quires m/z 361.1525, found m/z 361.1492; enantiomeric excess:
85%, determined by HPLC (Daicel Chirapak OD-H, hexane–2-propa-
nol = 95:5, flow rate 0.5 mL/min, T = 30 °C, 254 nm): tR = 24.92 min
(major), tR = 26.93 min (minor).
NH), 2.38 (s, 3H, CH3), 1.87–1.62 (m, 4H, 2CH2), 1.29 (dt,
J1 = 7.2 Hz, J2 = 3.2 Hz, 6H, 2CH3), 1.26–1.01 (m, 7H, CH, and
3CH2); 13C NMR (CDCl3, 100 MHz) d (ppm): 195.4, 169.8, 169.4,
147.3, 135.9, 78.8, 69.0, 62.6, 62.0, 40.0, 30.6, 27.8, 26.6, 26.3,
26.0, 25.7, 14.0; IR (KBr):
m 3366, 3093, 2982, 2926, 1736, 1679,
1449, 1367, 1228, 1111, 1035, 856, 604; ESI FTMS exact mass calcd
for (C18H27NO5+H)+ requires m/z 338.1968, found m/z 338.1983;
enantiomeric excess: 66%, determined by HPLC (Daicel Chirapak
IC-H, hexane–2-propanol = 70:30, flow rate 1.0 mL/min, T = 30 °C,
254 nm): tR = 4.77 min (minor), tR = 5.49 min (major).
4.3.15. (5S)-Diethyl 4-acetyl-5-(thiophen-2-yl)-1H-pyrrole-
2,2(5H)-dicarboxylate 4o
Flash column chromatography eluent, petroleum ether–ethyl
acetate = 8:1; yield: 62%; colorless oil; ½a D20
¼ þ192:3 (c 0.03,
ꢁ
CHCl3); 1H NMR (CDCl3, 400 MHz) d (ppm): 7.17 (dd, J1 = 4.8 Hz,
J2 = 1.2 Hz, 1H, Thiophene-H), 7.01 (dt, J1 = 3.6 Hz, J2 = 0.4 Hz, 1H,
Thiophene-H), 6.91 (dd, J1 = 4.8 Hz, J2 = 3.6 Hz, 1H, Thiophene-H),
6.74 (d, J = 2.0 Hz, 1H, @CH), 5.72 (s, 1H, CH), 4.33–4.24 (m, 4H,
2CH2), 3.53 (s, 1H, NH), 2.32 (s, 3H, CH3), 1.31 (dt, J1 = 7.2 Hz,
J2 = 2.8 Hz, 6H, 2CH3); 13C NMR (CDCl3, 100 MHz) d (ppm): 194.2,
169.2, 168.7, 147.2, 146.1, 135.1, 126.9, 125.5, 125.0, 78.8, 63.0,
4.3.19. (5S)-Diethyl 5-(4-nitrophenyl)-4-nonanoyl-1H-pyrrole-
2,2(5H)-dicarboxylate 4s
Flash column chromatography eluent, petroleum ether–ethyl
acetate = 12:1; yield: 67%; colorless oil; ½a D20
¼ þ167:2 (c 0.634,
ꢁ
CHCl3); 1H NMR (CDCl3, 400 MHz) d (ppm): 8.14 (d, J = 8.8 Hz,
2H, ArH), 7.50 (d, J = 8.8 Hz, 2H, ArH), 6.77 (d, J = 2.0 Hz, 1H,
@CH), 5.52 (s, 1H, CH), 4.37–4.25 (m, 4H, 2CH2), 3.60 (s, 1H, NH),
2.67–2.56 (m, 2H, CH2), 1.50–1.44 (m, 2H, CH2), 1.33 (t,
J = 6.8 Hz, 3H, CH3), 1.32 (t, J = 7.2 Hz, 3H, CH3), 1.24–1.16 (m,
10H, 5CH2), 0.86 (t, J = 6.8 Hz, 3H, CH3); 13C NMR (CDCl3,
100 MHz) d (ppm):196.9, 169.2, 169.1, 149.4, 147.4, 147.1, 134.8,
128.7, 123.6, 79.3, 67.3, 63.0, 62.6, 40.0, 31.8, 29.7, 29.1, 29.0,
23.8, 22.6, 14.1; enantiomeric excess: 97%, determined by HPLC
(Daicel Chirapak AD-H, hexane–2-propanol = 80:20, flow rate
62.7, 62.6, 27.8, 14.1, 14.0; IR (KBr):
m 3361, 3091, 2982, 2934,
1735, 1682, 1272, 1230, 1109, 1040, 855, 706; ESI FTMS exact mass
calcd for (C16H19NO5S+H)+ requires m/z 338.1062, found m/z
338.1077; enantiomeric excess: 74%, determined by HPLC (Daicel
Chirapak OD-H, hexane–2-propanol = 95:5, flow rate 1.0 mL/min,
T = 30 °C, 254 nm): tR = 10.14 min (major), tR = 11.62 min (minor).
4.3.16. (5S)-Diethyl 4-acetyl-5-(furan-2-yl)-1H-pyrrole-2,2(5H)-
dicarboxylate 4p
1.0 mL/min,
T = 30 °C,
254 nm):
tR = 6.917 min
(major),
Flash column chromatography eluent, petroleum ether–ethyl
tR = 18.660 min (minor).
acetate = 7:1; yield: 50%; colorless oil; ½a D20
¼ þ63:2 (c 0.2, CHCl3);
ꢁ
1H NMR (CDCl3, 400 MHz) d (ppm): 7.28 (dd, J1 = 2.0 Hz, J2 = 0.8 Hz,
1H, Furan-H), 6.83 (d, J = 2.0 Hz, 1H, Furan-H), 6.28 (dd, J1 = 3.2 Hz,
J2 = 1.6 Hz, 1H, Furan-H), 6.19 (d, J = 2.8 Hz, 1H, @CH), 5.44 (s, 1H,
CH), 4.32–4.23 (m, 4H, 2CH2), 3.37 (s, 1H, NH), 2.34 (s, 3H, CH3),
1.29 (dt, J1 = 7.2 Hz, J2 = 4.0 Hz, 6H, 2CH3); 13C NMR (CDCl3,
100 MHz) d (ppm): 194.0, 169.1, 168.7, 153.6, 145.0, 142.1,
136.5, 110.5, 107.3, 79.0, 62.6, 62.6, 61.1, 27.6, 14.0, 14.0; IR
4.3.20. (5S)-Diethyl 5-(4-nitrophenyl)-4-(3-phenylpropanoyl)-
1H-pyrrole-2,2(5H)-dicarboxylate 4t
Flash column chromatography eluent, petroleum ether–ethyl
acetate = 8:1; yield: 74%; colorless oil; ½a D20
¼ þ174:1 (c 0.692,
ꢁ
CHCl3); 1H NMR (CDCl3, 400 MHz) d (ppm): 8.13 (d, J = 8.8 Hz,
2H, ArH), 7.47 (d, J = 8.8 Hz, 2H, ArH), 7.25–7.21 (m, 2H, ArH),
7.19–7.16 (m, 1H, ArH), 7.09–7.06 (m, 2H, ArH), 6.76 (d,
J = 2.0 Hz, 1H, @CH), 5.52 (dd, J = 5.6, 2.0 Hz, 1H, CH), 4.37–4.17
(m, 4H, 2CH2), 3.59 (d, J = 5.6 Hz, 1H, NH), 3.06–2.88 (m, 2H,
CH2), 2.93–2.75 (m, 2H, CH2), 1.32 (t, J = 7.2 Hz, 3H, CH3), 1.31 (t,
J = 7.2 Hz, 3H, CH3); 13C NMR (CDCl3, 100 MHz) d (ppm): 195.6,
169.0, 168.9, 149.3, 147.4, 146.9, 140.4, 135.4, 128.8, 128.5,
128.3, 126.3, 123.6, 79.3, 67.3, 63.0, 62.6, 41.6, 14.1; enantiomeric
excess: 95%, determined by HPLC (Daicel Chirapak OD-H, hexane–
2-propanol = 85:15, flow rate 1.0 mL/min, T = 30 °C, 254 nm):
tR = 10.957 min (major), tR = 12.006 min (minor).
(KBr):
m 3352, 3093, 2961, 2926, 1735, 1683, 1367, 1277, 1231,
1112, 1032, 856, 744, 599; ESI FTMS exact mass calcd for
(C16H19NO6)+ requires m/z 321.1212, found m/z 321.1198; enantio-
meric excess: 61%, determined by HPLC (Daicel Chirapak OD-H,
hexane–2-propanol = 95:5, flow rate 1.0 mL/min, T = 30 °C,
254 nm): tR = 11.72 min (major), tR = 13.48 min (minor).
4.3.17. (5S)-Diethyl 4-acetyl-5-(4-methoxystyryl)-1H-pyrrole-
2,2(5H)-dicarboxylate 4q
Flash column chromatography eluent, petroleum ether–ethyl
acetate = 6:1; yield: 24%; yellow oil; ½a D20
¼ þ15:3 (c 0.1, CHCl3);
ꢁ
4.3.21. (5S)-Diethyl 4-(2-ethylbutanoyl)-5-(4-nitrophenyl)-1H-
pyrrole-2,2(5H)-dicarboxylate 4u
1H NMR (CDCl3, 400 MHz) d (ppm): 7.28 (d, J = 8.8 Hz, 2H, ArH),
6.81 (d, J = 8.8 Hz, 2H, ArH), 6.67 (d, J = 2.0 Hz, 1H, @CH), 6.61 (d,
J = 16.0 Hz, 1H, @CH), 5.98 (dd, J1 = 16.0 Hz, J2 = 7.6 Hz, 1H, @CH),
4.98 (d, J = 7.6 Hz, 1H, CH), 4.35–4.23 (m, 4H, 2CH2), 3.79 (s, 3H,
OCH3), 3.19 (s, 1H, NH), 2.36 (s, 3H, CH3), 1.30 (q, J = 7.2 Hz, 6H,
2CH3); 13C NMR (CDCl3, 100 MHz) d (ppm): 194.5, 169.6, 169.3,
159.3, 147.3, 135.1, 131.4, 129.5, 127.8, 126.8, 113.9, 78.9, 66.4,
Flash column chromatography eluent, petroleum ether–ethyl
acetate = 12:1; yield: 50%; colorless oil; ½a D20
¼ þ183:0 (c 0.436,
ꢁ
CHCl3); 1H NMR (CDCl3, 400 MHz) d (ppm): 8.13 (d, J = 8.8 Hz,
2H, ArH), 7.51 (d, J = 8.8 Hz, 2H, ArH), 6.76 (d, J = 2.0 Hz, 1H,
@CH), 5.55 (dd, J = 6.0, 2.0 Hz, 1H, CH), 4.38–4.26 (m, 4H, 2CH2),
3.62 (d, J = 6.0 Hz, 1H, NH), 2.86–2.81 (m, 1H, CH), 1.65–1.53 (m,
2H, CH2), 1.46–1.37 (m, 2H, CH2), 1.34 (t, J = 6.8 Hz, 3H, CH3),
1.32 (t, J = 7.2 Hz, 3H, CH3), 0.81 (t, J = 7.2 Hz, 3H, CH3), 0.51 (t,
J = 7.6 Hz, 3H, CH3); 13C NMR (CDCl3, 100 MHz) d (ppm): 201.0,
169.2, 169.1, 149.5, 148.0, 147.4, 134.6, 128.8, 123.5, 79.4, 67.4,
62.9, 62.6, 51.3, 25.1, 23.8, 14.1, 14.0, 11.9, 11.0; enantiomeric ex-
cess: 87%, determined by HPLC (Daicel Chirapak AD-H, hexane–2-
propanol = 80:20, flow rate 1.0 mL/min, T = 30 °C, 254 nm):
tR = 5.777 min (major), tR = 21.000 min (minor).
62.6, 62.5, 55.3, 27.8, 14.1, 14.0; IR (KBr):
m 3349, 2959, 2925,
1736, 1680, 1605, 1512, 1366, 1251, 1174, 1030, 853; ESI FTMS
exact mass calcd for (C21H25NO6–2H)+ requires m/z 385.1525,
found m/z 385.1500; enantiomeric excess: 86%, determined by
HPLC (Daicel Chirapak OD-H, hexane–2-propanol = 90:10, flow
rate 1.0 mL/min, T = 30 °C, 254 nm): tR = 8.82 min (major), tR =
10.33 min (minor).
4.3.18. (5S)-Diethyl 4-acetyl-5-cyclohexyl-1H-pyrrole-2,2(5H)-
dicarboxylate 4r
Flash column chromatography eluent, petroleum ether–ethyl
4.3.22. (5S)-Diethyl 4-(cyclohexanecarbonyl)-5-(4-nitrophenyl)-
1H-pyrrole-2,2(5H)-dicarboxylate 4v
acetate = 10:1; yield: 31%; colorless oil; ½a D20
¼ þ105:0 (c 0.04,
ꢁ
CHCl3); 1H NMR (CDCl3, 400 MHz) d (ppm): 6.61 (d, J = 2.0 Hz,
1H, @CH), 4.35 (s, 1H, CH), 4.30–4.21 (m, 4H, 2CH2), 3.09 (s, 1H,
Flash column chromatography eluent, petroleum ether–ethyl
acetate = 12:1; yield: 69%; colorless oil; ½a D20
¼ þ191:8 (c 0.61,
ꢁ

2064
F. Shi et al. / Tetrahedron: Asymmetry 22 (2011) 2056–2064
CHCl3); 1H NMR (CDCl3, 400 MHz) d (ppm): 8.13 (d, J = 8.8 Hz, 2H,
ArH), 7.49 (d, J = 8.8 Hz, 2H, ArH), 6.73 (d, J = 2.0 Hz, 1H, @CH), 5.53
(s, 1H, CH), 4.35–4.28 (m, 4H, 2CH2), 3.61 (d, J = 4.4 Hz, 1H, NH),
2.86–2.78 (m, 1H, CH), 1.78–1.62 (m, 6H, 3CH2), 1.33 (t,
J = 7.2 Hz, 3H, CH3), 1.32 (t, J = 7.2 Hz, 3H, CH3), 1.18–1.06 (m, 2H,
CH2), 0.98–0.86 (m, 2H, CH2); 13C NMR (CDCl3, 100 MHz) d
(ppm): 200.3, 169.2, 169.1, 149.5, 147.4, 146.4, 135.2, 133.9,
129.4, 128.7, 124.8, 123.6, 79.4, 67.4, 62.9, 62.6, 47.5, 29.5, 27.9,
25.8, 25.6, 25.2, 14.1, 14.0; enantiomeric excess: 94%, determined
by HPLC (Daicel Chirapak AD-H, hexane–2-propanol = 70:30, flow
rate 1.0 mL/min, T = 30 °C, 254 nm): tR = 7.111 min (major),
tR = 22.524 min (minor).
The IC50 value to MCF7 cells corresponded to the compound con-
centration causing 50% mortality in MCF7 cells.
Acknowledgment
We are grateful for the financial support from the Natural Sci-
ence Foundation of China (Nos. 21002083 and 21072163).
References
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4.3.23. (5S)-Diethyl 5-(4-nitrophenyl)-4-(2-phenylacetyl)-1H-
pyrrole-2,2(5H)-dicarboxylate 4w
Flash column chromatography eluent, petroleum ether–ethyl
acetate = 8:1; yield: 51%; colorless oil; ½a D20
¼ þ170:8 (c 0.462,
ꢁ
CHCl3); 1H NMR (CDCl3, 400 MHz) d (ppm): 8.04 (d, J = 8.8 Hz,
2H, ArH), 7.35 (d, J = 8.8 Hz, 2H, ArH), 7.25–7.21 (m, 3H, ArH),
7.04–7.01 (m, 2H, ArH), 6.34 (d, J = 2.0 Hz, 1H, @CH), 5.51 (s, 1H,
CH), 4.35–4.25 (m, 4H, 2CH2), 3.96–3.87 (m, 2H, CH2), 3.58 (d,
J = 4.8 Hz, 1H, NH), 1.32 (t, J = 7.2 Hz, 3H, CH3), 1.31 (t, J = 7.2 Hz,
3H, CH3); 13C NMR (CDCl3, 100 MHz) d (ppm):193.8, 169.0, 168.9,
148.9, 147.3, 146.5, 135.7, 132.9, 129.3, 128.7, 127.2, 123.5, 79.4,
67.4, 63.0, 62.6, 47.2, 14.1; enantiomeric excess: 97%, determined
by HPLC (Daicel Chirapak AD-H, hexane–2-propanol = 70:30, flow
rate 1.0 mL/min, T = 30 °C, 254 nm): tR = 10.231 min (major),
tR = 35.614 min (minor).
4.4. Cytotoxic evaluation of selected 2,5-dihydropyrroles 4 to
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was aspirated from each well and 150 lL of DMSO was added
to dissolve the formazan crystals; the absorbance of each well
was obtained using a Model 680 microplate reader (Bio Rad.,
USA) counter at test and reference wavelengths of 570 nm. The
inhibition rate was calculated according to the following formula:
Inhibition rate = (OD570 control ꢀ OD570 sample)/OD570 control ꢂ 100%,
where OD stands for optical density at 570 nm. Then the inhibi-
tion rates of the tested compounds in various concentrations
were processed by SPSS 13.0 software to calculate the IC50 values.