Design, synthesis and preliminary evaluation of new cinnamoyl pyrrolidine derivatives as potent gelatinase inhibitors

Article abstract of DOI:10.1016/j.bmc.2006.09.015

A series of new cinnamoyl pyrrolidine derivatives have been synthesized based on the l-hydroxyproline scaffold and inhibiting activities on gelatinase (MMP-2 and -9) and APN were tested. Structure-activity relationship studies showed that the side chain with aromatic ring at C4 in pyrrolidine ring showed better inhibitory activities on gelatinase than aliphatic side chain. Most compounds exhibited poor activities on APN compared with MMP-2. Within this series, three compounds, A8, B9 and C10, have the good potency (IC₅₀ = 5.2-9.7 nM) and could be used as lead compounds in the future.

Full text of DOI:10.1016/j.bmc.2006.09.015

Bioorganic & Medicinal Chemistry 14 (2006) 8286–8294
Design, synthesis and preliminary evaluation of new cinnamoyl
pyrrolidine derivatives as potent gelatinase inhibitors
Li Zhang,a,b Jie Zhang,a Hao Fang,a Qiang Wanga and Wenfang Xua,*
aDepartment of Medicinal Chemistry, School of Pharmacy, Shandong University, 44, West Culture Road, Ji’nan,
Shandong 250012, PR China
bMedical College of Qingdao University, Qingdao, Shandong 266021, PR China
Received 1 July 2006; revised 4 September 2006; accepted 8 September 2006
Available online 27 September 2006
Abstract—A series of new cinnamoyl pyrrolidine derivatives have been synthesized based on the L-hydroxyproline scaffold and
inhibiting activities on gelatinase (MMP-2 and -9) and APN were tested. Structure–activity relationship studies showed that the side
chain with aromatic ring at C4 in pyrrolidine ring showed better inhibitory activities on gelatinase than aliphatic side chain. Most
compounds exhibited poor activities on APN compared with MMP-2. Within this series, three compounds, A8, B9 and C10, have
the good potency (IC50 = 5.2–9.7 nM) and could be used as lead compounds in the future.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
moyl group, to L-hydroxyproline scaffold which is
known as the substrate of MMPs. The cinnamoyl group
was chosen because cinnamic acid is proved to inhibit
A5491 human cancer of lung gland and the caffic acid
is proved to inhibit MMP-2 and -9.7 In this study, we
linked cinnamic acid, caffic acid and its analogs with
hydroxyproline derivatives in order to find compounds
with potent inhibitory activity (Tables 1–3).
As a family of zinc-dependent proteinases, matrix
metalloproteinases (MMPs) were involved in the degra-
dation of the extracellular matrix and the processes of
tumor growth, invasion, and metastasis. The studies
showed that MMPs overexpressed by malignant tumors
have been associated with an aggressive malignant phe-
notype and poor prognosis in patients with cancer.1–3
Currently, the mammal MMP gene family consists of
at least 25 structurally related members,4 among which,
gelatinase (MMP-2) proved to be in high correlation
with cancer.5
2. Chemistry
The target compounds were synthesized via the route
outlined in Scheme 1. Methyl 4-hydroxy-L-pyrrolidine-
The interaction of MMP inhibitors with MMPs is illus-
trated in Figure 1 according to the complex of
CGS27023A with MMP-3.6 The figure shows that the
p-(methoxyphenyl)-sulfonyl fragment inserts into S1
pocket of the enzyme, while the pyridine and isopropyl
group are located in S2 pocket and S1 domain, respec-
tively. Two hydrogen bonds existed between the inhibi-
tor and the enzyme, which includes the oxygen atom of
sulfonylamide with NH of Leu164 and NH of hydrox-
amic acid with carbonyl O of Ala165. Considering the
S1 pocket of gelatinase is much deeper than that of
MMP-3, we introduced a bigger fragment, the cinna-
Keywords: Cinnamoyl pyrrolidine derivatives; MMPs inhibitors; IC50
.
Corresponding author. Tel./fax: +86 531 88382264; e-mail:
xuwenf@sdu.edu.cn
*
Figure 1. Mode of binding of CGS 27023A with MMP-3 (Ref. 6).
0968-0896/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2006.09.015

L. Zhang et al. / Bioorg. Med. Chem. 14 (2006) 8286–8294
8287
Table 1. The inhibitory activities of series A compounds
Table 3. The inhibitory activities of series B compounds
O
O
O
O
MeO
N
OMe
N
OMe
MeO
RO
RO
A
C
Compound
R
IC50 (nmol)
MMP APN
Compound
R
IC50 (nmol)
MMP2, 9 APN
C1
C2
C3
C4
C5
C6
CH3CO
320.2
293.4
221.1
201.2
111.8
—
808.3
543.6
356.8
289.6
195.1
—
A0
A1
A2
A3
A4
A5
A6
H
11.2
128.4
98.1
147.4
264.6
216.3
211
CH3CH2CO
CH3CH2CH2CO
C6H5CO
CH3CO
CH3CH2CO
CH3CH2CH2CO
C6H5CO
p-Cl–C6H5CO
85.6
52.4
p-Cl–C6H5CO
163.2
149.7
80.1
31.8
259.5
O
O
MeO
MeO
MeO
MeO
OMe
OMe
A7
A8
C6H5CH2CH2CO
C6H5CH@CHCO
p-CH3O–C6H4CH@CHCO
3,4-(OMe)2 C6H3CH@CHCO
43.6
5.2
359.4
75.2
C7
C8
C6H5CH2CH2CO
C6H5CH@CHCO
p-CH3O–C6H4CH@CHCO
3,4-(OMe)2C6H3CH@CHCO
168.3
86.5
28.7
9.7
226
189.2
103.4
88.3
A9
A10
12.3
13.1
132.5
296.2
C9
C10
Table 2. The inhibitory activities of series B compounds
selectivity. Similarly as MMPs, APN is also a family
of zinc-dependent metalloproteinases associated with
malignant tumor with two zinc ions in the catalytic
domain. In MMP inhibition assay, gelatinase (MMP-
2) and (trinitrobenzenesulfonic acid) TNBS were pur-
chased from Sigma, and the substrate was synthesized
as described by Vijaykumar et al.8 The gelatinase, sub-
strate, and inhibitor were dissolved in sodium borate
solution (pH 8.5, 50 mmol/L) and incubated for
30 min at 37 °C, and then 0.03% TNBS was added and
incubated for another 20 min, the resulting solution
detected under 450 nm wavelength to gain absorption.
The inhibitory activities of compounds against APN
were also carried out with L-leucine p-nitroanilide as
substrate. The results of their inhibitory activities
(IC50) are reported in Figures 2–4.
O
O
N
OMe
MeO
RO
B
Compound
R
H
IC50 (nmol)
MMP-2, 9 APN
B0
B1
B2
B3
B4
B5
B6
439.8
316.4
280.2
195
296.9
563.1
328.5
261.3
211.4
165.3
856.6
CH3CO
CH3CH2CO
CH3CH2CH2CO
C6H5CO
109.9
42.8
562.6
p-Cl–C6H5CO
O
MeO
MeO
3.1.1. Structure–activity relationship in vitro for series A
compounds. When the side chain (R) was aliphatic, long-
er, and more flexible side chain linked to the pyrrolidine
ring at C4 showed better activity at gelatinase.
OMe
B7
B8
C6H5CH2CH2CO
C6H5CH@CHCO
p-CH3O–C6H4CH@CHCO
73.4
39.1
7.8
213
—
B9
B10
128.6
88.7
As a strong inhibitor against MMP-2, compound A0
might be a different case because hydroxy group could
possibly form hydrogen bond with the residue of the en-
zyme which stabilized the binding between the enzyme
and the compound. Compounds with aromatic side
chain showed higher activity compared to aliphatic
derivatives. The possible reason may be due to the p sys-
tem of the aromatic ring enhancing the interaction with
the hydrophobic region of the enzyme. Substitution on
aromatic ring also has impact on bioactivity. For exam-
ple, compound A5 which is substituted with chlorine in
para position shows a slightly better inhibitory activity
compared with A4. While compound A6 substituted
with trimethoxy group showed lower activity. It is wor-
thy to note that increasing conjugate system between es-
ter and aromatic ring will keep up or improve activities
3,4- (OMe)2 C6H3CH@CHCO 121.3
carboxylate hydrochloride was prepared according to
the literature10 and then converted to amide compounds
with cinnamoyl chloride, p-methyl cinnamoyl chloride,
and caffeoyl chloride to form the amide. The final target
compounds were synthesized by esterification with dif-
ferent acyl chloride eventually.
3. Results and discussion
3.1. Structure–activity relationship in vitro
Preliminary activity assay was carried out in vitro on
gelatinase and APN so as to identify the compound

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L. Zhang et al. / Bioorg. Med. Chem. 14 (2006) 8286–8294
O
O
H
H
R1
R2
N
COOH
a
N
COOCH3
HCl
N
c
OMe
HO
HO
HO
O
d
O
O
R1
R2
O
R1
R2
Cl
R1
R2
b
OH
N
OMe
RCOO
Scheme 1. Reagents: (a) MeOH, HCl; (b) SOCl2, C6H6; (c) Py, Et3N; (d) RCOCl, Et3N, CH2Cl2 A0–A10: R1 = H, R2 = H; B0–B10: R1 = H,
R2 = OMe; C1–C10: R1 = OMe, R2 = OMe.
activity against MMP-2, but showed good activity
against APN. Compounds A7 and A10 both showed
high activity against MMP-2, but low affinity to APN.
It was difficult to explain the reasons for these differenc-
es. One possible reason might be that MMP was a kind
of endopeptidase and could cut the peptide to parts
form the specific amino acid residue of MMP; but
APN was a different kind of exopeptidase and focused
on hydrolyzing the amino acid only from the side of N
Figure 2. The comparison chart of activity for A0–10 series com-
of the peptide. The differences in the function between
pounds designed.
the two kinds of enzymes were due to the differences
of their structure. As the two kinds of metal enzymes
had differences in structure, there were different require-
ments in structure to their respective antagonists.
3.1.2. Structure–activity relationship in vitro of B series
compounds. The inhibitory activity of B series com-
pounds was similar to that of A series compounds. It
was the same that the compound with longer aliphatic
side chain (R) showed better inhibitory activity. In addi-
tion, the compounds with aromatic side chain have
higher affinity than the compounds with aliphatic side
Figure 3. Comparison with activities for B series compounds.
chain. Compound B5 displayed good activity against
MMP-2, and it might be due to the chloride atom. Com-
pound B6 containing galloyl substituent which was pro-
tected by methoxy group also exhibited low activity. The
difference was that compound B10 showed poor inhibi-
tory activity against MMP-2. Compound B9 showed
high inhibitory activity against APN. However, it had
special examples in B series compounds. The inhibition
ratio of compound B8 against APN was not changed
with the concentration strongly, and the IC50 value
was very high, while compound B10 showed better
inhibitory activity against APN than MMP-2.
Figure 4. Comparison chart of activities for C series compounds
designed.
3.1.3. Structure–activity relationship in vitro of C series
compared with strong inhibitor compound A0, such as
compounds A8–A10.
compounds. The inhibitory activity of C series com-
pounds was familiar to those of A and B series on the
whole. From C1 to C10, when R side chain was aliphat-
ic, the inhibitory activity of the compounds against
MMP-2 was stronger as the length increased. The inhib-
itory activity of the aromatic substitute was obviously
stronger than aliphatic. Compound C10 showed good
inhibitory activity against MMP-2. Compound C6 con-
taining trimethoxy substitute side chain had low affinity.
C series compounds showed better inhibitory activity
against MMP-2 than to APN on the whole.
For series A compounds, the inhibitory activity against
APN is lower than against MMP-2, but the varying ten-
dency is similar to that of MMP-2. For example, the
compounds with aliphatic side chain (R) exhibited low
inhibitory activity, but the compound with aromatic
ring showed better. Although compound A8 had good
activity on both enzymes, the other compounds showed
different result. For example, compound A6 had low

L. Zhang et al. / Bioorg. Med. Chem. 14 (2006) 8286–8294
8289
4. Conclusion
Comparing the inhibitory activity of A, B, and C series
compounds in vitro, it was demonstrated that com-
pound with small N1 side chain would exhibit high
activity, and most compounds had better inhibitory
activity to MMP-2 than to APN. According to the 3D
structure of the target enzyme, FlexX Docking was used
for modeling the target compounds with the enzyme. We
selected target compounds B9 and C10 to the FlexX
docking utilizing SYBYL 7.0 of TRIPOS Company of
USA (Fig. 5).
Figure 6. the FlexX docking of compound A8 with MMP-2.
Figure 5 shows compounds B9 and C10 binding with
MMP-2. The carboxylic ester group chelates with the
catalytic zinc 166, and the hydrophobic side chain of
C4 extends into S10 pocket of the enzyme, while the side
chain of N1 inserts into S1 pocket of the enzyme. Fur-
thermore, the compounds bind with the enzyme back-
bone by hydrogen bond. Unlike others, the side chain
N1 of compound A0 extends into S10 pocket.
We also carried out the FlexX Docking of compound
A8 with the enzyme MMP-2 (Fig. 6) and human leuko-
triene A4 hydrolase (LTA4H) which is the homology en-
zyme of APN9 (Fig. 7). The side chains of C4 and N1
insert into S10 pocket and S1 pocket, respectively. The
carboxylic ester group chelates with the catalytic zinc
Figure 7. the FlexX docking of compound A8 with LTA4H.
˚
166 with a distance of 1.21 A. However, the molecule
matography on 0.25-mm silica gel plates (60GF-254)
and visualized with UV light, or iodine vapor. 1H
NMR spectra were determined on a Brucker AM600
spectrometer using TMS as an internal standard. ESI
MS were determined on an API 4000 spectrometer.
could not extend into the hydrophobic pocket of the ac-
tive region when compound A8 docked with LTA4H.
Meanwhile, two oxygen atoms in C4 ester were far from
˚
the catalytic zinc with the distance of 6.14 and 5.43 A,
respectively, which leads to the compound failing to che-
late with the catalytic zinc perfectly. It illustrated indi-
rectly that if the three dimensional structure of the
active site of the enzymes was different, the structural
requirements to their inhibitors were also different. In
the same way, if a compound had special selectivity to
a certain specified enzyme, it might become a promising
lead compound which could avoid the multi-side effects
of drugs with broad-spectrum effects.
5.1. (2S,4R)-Methyl-4-hydroxy-2-pyrrolidine-
carboxylatehydroxychloride (1)
The title compound was prepared as described by Jordis
in (1S, 4S)-2-thia-5-azabicyclo [2.2.1] heptane.7
5.1.1. (2S,4R,E)-Methyl-1-cinnamoyl-4-hydroxypyrroli-
dine-2-carboxylate (A0). Compound 1 (1.85 g, 11 mmol)-
was suspended in 20 ml Py and 3 ml Et3N. After stirred
for 20 min at room temperature, the resulting mixture
was filtrated. The filtrate was cooled to ꢀ5 °C, and at this
temperature, 20 ml CH2Cl2 with 1.67 g (10 mmol) com-
pound 1 was added. After stirred for 3 h, the resulting
mixture was filtered to remove white precipitation, and
5. Experimental
All reactions except those in aqueous media were carried
out by standard techniques for the exclusion of mois-
ture. All reactions were monitored by thin-layer chro-
S1
S1
S1’
S1’
Figure 5. The FlexX docking of compound B9 (left) and compound C10 (right) with MMP-2.

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L. Zhang et al. / Bioorg. Med. Chem. 14 (2006) 8286–8294
the filtrate was rotary evaporated. Small amount toluene
was added to remove Py. The resulting crude oil was dis-
solved with 200 ml CH2Cl2, washed with 3 N HCl, H2O,
saturated salt solution, and dried over Na2SO4, anhy-
drous. The yellow crude product was recrystallized with
CH2Cl2 to provide 2.23 g of white crystal, yield 81.0%,
mp 138.8–140.2 °C. IR (KBr, cmꢀ1): 3431.76 (OH),
2949.61 (CH), 1743.99 1646.36 (C@O), 1592.39,
1432.23 (C@C), 1199.09 (C–O). ESI-MS [M+1]:276.4;
1H NMR (DMSO-d6, ppm): 7.61 (m, 2H), 7.43 (d, 1H,
J = 15.6 Hz), 7.40 (m, 3H), 7.01 (d, 1H), 5.20 (m, 1H),
4.44 (t, 1H, J = 7.8 Hz), 4.29 (s, 1H), 3.80, 3.68 (m,
2,H), 3.63 (s, 3H), 2.14, 1.92 (m, 2H).
(DMSO-d6, ppm): 7.79 (m, 2H), 7.73 (m, 2H), 7.65 (d,
1H, J = 15.6 Hz), 7.51 (m, 3H), 7.40 (m, 3H), 7.08 (d,
1H, J = 15.6 Hz), 5.62 (m, 1H), 4.61 (t, 1H, J = 8.4 Hz),
4.17, 4.08 (m, 2H), 3.67 (s, 3H), 2.56, 2.28 (m, 2H).
5.1.7. (2S,4R,E)-Methyl 4-(4-chloro benzoyloxy)-1-cin-
namoylpyrrolidine-2-carboxylate (A5). White crystal,
yield 69.1%, mp 64.1–66.2 °C. IR (KBr, cmꢀ1):
2951.13 (CH), 1745.97, 1709.36 (C@O), 1611.52,
1418.58 (C@C), 1267.74 (C–O). ESI-MS [M+1]: 414.5;
1H NMR (DMSO-d6, ppm): 7.98 (m, 2H), 7.73 (m,
2H), 7.71 (m, 2H), 7.60 (d, 1H, J = 15.6 Hz), 7.51 (m,
3H), 7.06 (d, 1H, J = 15.6 Hz), 5.61 (m, 1H), 4.61 (t,
1H, J = 8.4 Hz), 4.17, 4.06 (m, 2H), 3.67 (s, 3H), 2.29,
1.98 (m, 2H).
5.1.2. (2S,4R,E)-Methyl 4-acetoxy-1-cinnamoylpyrroli-
dine-2-carboxylate (A1). CompoundA0(2.75 g, 10 mmol)
was resolved in 40 ml CH2Cl2 and 4.5 ml Et3N. After 5 ml
CH2Cl2 with 0.8 ml acetyl chloride was added dropwise at
0 °C and stirred for 4 h, CH2Cl2 was added to dilute the
reaction mixture. Then the organic phase was washed with
1 N HCl, H2O, saturated salt solution, dried over Na2SO4
anhydrous, and rotary evaporated. The resulting crude oil
was chromatographed over flash silica with petro ether/
EtOAc (2:1–1:2) to provide 2.2 g of white crystal, yield
69.4%, mp 76.5–78.5 °C. IR (KBr, cmꢀ1): 2950.86 (CH),
1742.83, 1651.77 (C@O), 1604.22, 1429.61 (C@C),
1248.79 (C–O). ESI-MS [M+1]:318.5; 1H NMR
(DMSO-d6, ppm): 7.74 (m, 2H, Ar–H), 7.49 (d, 1H@CH,
J = 15.6 Hz), 7.40 (m, 3H), 7.03 (d, 1H, J = 15.6 Hz),
5.34 (m, 1H), 4.46 (t, 1H, J = 8.4 Hz), 3.97 (m, 2H), 3.65
(s, 3H), 2.36, 2.17 (m, 2H), 2.02 (s, 3H).
5.1.8. (2S,4R,E)-Methyl1-cinnamoyl-4-(3-phenylpropa-
noyloxy)pyrrolidine-2-carboxylate (A7). White crystal,
yield 72.4%, mp 119.1–120.8 °C. IR (KBr, cmꢀ1):
2953.14 (CH), 1733.05, 1707.32 (C@O), 1606.48,
1418.78 (C@O), 1267.04 (C–O). ESI-MS [M+1]: 408.4;
1H NMR (DMSO -d6, ppm): 7.74 (m, 2H), 7.49 (d, 1H,
J = 15.6 Hz), 7.41 (m, 3H), 7.21 (m, 4H), 7.12 (m, 1H),
7.0 (d, 1H, J = 15.6 Hz), 5.33 (m, 1H), 4.38 (t, 1H,
J = 8.4 Hz), 3.93, 3.86 (m, 2H), 3.64 (s, 3H), 2.82 (t, 2H,
J = 7.2 Hz), 2.63 (t, 2H, J = 7.8 Hz), 2.14, 2.11 (m, 2H).
5.1.9. (2S,4R,E)-Methyl1-cinnamoyl-4-(3,4,5-trimethoxy-
benzoyloxy)pyrrolidine-2-carboxylate (A6).
5.1.10. Compound 3,4,5-trimethoxybenzoic acyl chloride
(3). 2.38 g 3, 4,5-3,4,5-trimethoxybenzoic acid was
dissolved in 15 ml SOCl2, and refluxed for 5 h, the result-
ing solution was rotary evaporated to get pale yellow
crystal.
5.1.3. Compounds A2, A3, A4, A5, and A7 were prepared
as described for compound A1
5.1.4.
(2S,4R,E)-Methyl
1-cinnamoyl-4-(propionyl-
oxy)pyrrolidine-2-carboxylate (A2). White solid, yield
70.1%, mp 77.2–78.6 °C. IR (KBr, cmꢀ1):2950.37
(CH), 1746.63 and 1650.68 (C@O), 1606.35, 1428.49
(C@C), 1183.77 (C–O). ESI-MS [M+1]: 332.6; 1H
NMR (DMSO-dtextsubscript6, ppm): 7.74 (m, 2H),
7.50 (d, 1H, J = 15.6 Hz), 7.41 (m, 3H), 7.03 (d, 1H,
J = 15.6 Hz), 5.35 (m, 1H), 4.45 (t, 1H, J = 7.8 Hz),
3.97, 3.96 (m, 2H), 3.64 (s, 3H), 2.34 (q, 2H,
J = 4.8 Hz, 1.8 Hz), 2.31, 2.17 (m, 2H), 1.01 (t, 3H,
J = 3 Hz, 1.8 Hz).
5.1.11. (2S,4R,E)-methyl1-cinnamoyl-4-(3,4,5-trimethoxy-
benzoyloxy)pyrrolidine-2-carboxylate (A6). Compound
A0 (1.38 g, 5 mmol)was dissolved in 20 ml CH2Cl2 and
3 ml Et3N. After 5 ml CH2Cl2 with 3.86 g compound 3
was added dropwise at 0 °C and stirred for 4 h, CH2Cl2
was added to dilute the reaction mixture. Then the
organic phase was washed with 1 N HCl, H2O, saturat-
ed salt solution, dried over Na2SO4, anhydrous and
rotary evaporated. The resulting yellow crude oil was
chromatographed over flash silica with petro ether/
EtOAc (2:1–1:2) to provide 1.4 g of white powder, yield
54.2%, mp 63–65 °C. IR (KBr, cmꢀ1): 2944.28 (CH),
1715.53 and 1654.63 (C@O), 1416.02 (C@O), 1223.03
5.1.5. (2S,4R,E)-Methyl 4-(butyloxy)-1-cinnamoylpyrr-
olidine-2-carboxylate (A3). Pale yellow solid, yield
62.3%, mp 66.3–68.5 °C. IR (KBr, cmꢀ1): 2963.15
(CH), 1739.01,1654.47 (C@O), 1612.41, 1416.49
(C@C), 1177.24 (C–O). ESI-MS [M+1]: 346.2; 1H
NMR (DMSO-d6, ppm): 7.74 (m, 2H), 7.51 (d, 1H,
J = 15.6 Hz), 7.41 (m, 3H), 7.04 (d, 1H, J = 15.6 Hz),
5.36 (m, 1H), 4.47 (t, 1H, J = 7.8 Hz), 3.98, 3.97 (m,
2H), 3.65 (s, 3H), 2.35, 2.19 (m, 2H), 2.28 (t, 2H,
J = 7.2 Hz), 1.52 (m, 2H), 0.86 (t, 3H, J = 3.2 Hz).
1
and 1127.88 (C–O). ESI-MS [M+1]: 470.7. H NMR
(DMSO-d6, ppm): 7.73 (m, 2H), 7.49 (d, 1H,
J = 15.6 Hz), 7.40 (m, 3H), 7.24 (s, 1H), 7.23 (s, 1H),
7.05 (d, 1H, J = 15.6 Hz), 5.57 (m, 1H), 4.66 (t, 1H,
J = 8.4 Hz), 4.11 (m, 2H), 3.81 (s, 6H), 3.72 (s, 3H),
3.67 (s, 3H), 2.56, 2.29 (m, 2H).
5.1.12. Compounds A8, A9, and A10 were prepared as
described for compound A6
5.1.6. (2S,4R,E)-Methyl 4-(benzoyloxy)-1-cinnamoyl-
pyrrolidine-2-carboxylate (A4). White crystal, yield
73.2%, mp 106–107 °C. IR (KBr, cmꢀ1): 2953.13 (CH),
1707.35, 1651.46 (C@O), 1606.50, 1418.66 (C@C),
1267.03 (C–O). ESI-MS [M+1]: 380.4; 1H NMR
5.1.13. (2S,4R,E)-Methyl 1-cinnamoyl-4-(cinnamoyl-
oxy)pyrrolidine-2-carboxylate (A8). White powder, yield
60.1%, mp 53.6–54.7 °C. IR (KBr, cmꢀ1): 2951 (CH),
1746.4 and 1653.65 (C@C), 1167.74 (C–O). ESI-MS

L. Zhang et al. / Bioorg. Med. Chem. 14 (2006) 8286–8294
8291
[M+1]: 394.4. 1H NMR (DMSO-d6, ppm): 7.74 (m, 4H),
7.71 (d, 1H, J = 15.6 Hz), 7.51 (d, 1H, J = 15.6 Hz), 7.42
(m, 6H), 7.06 (d, 1H, J = 15.6 Hz), 6.67 (d, 1H,
J = 15.6 Hz), 5.51 (m, 1H), 4.55 (t, 1H, J = 8.4 Hz),
4.06, 4.02 (m, 2H), 3.67 (s, 3H), 2.26, 1.98 (m, 2H).
5.2.3. (2S,4R,E)-Methyl4-acetoxy-1-(3-(4-methoxyphe-
nyl)acryloyl)pyrrolidine-2-carboxylate (B1). Compound
B0 (1.50 g, 5 mmol) was taken in CH2Cl2 (20 ml) and
Et3N (3 ml) was added at 0 °C. Five milliliters of CH2Cl2
with 0.5 ml acetyl chloride was added dropwise and the
resulting mixture was stirred for 2 h at room temperature.
The following mixture was washed with 1 N HCl, H2O,
saturated salt solution, and dried over Na2SO4, anhy-
drous, filtered, and evaporated to give pale yellow oil,
which was chromatographed over flash silica with petro
ether-Ac (3:1 to 1:1) to provide 0.9 g white crystal, yield
53.4%, mp 123–124 °C. IR (KBr, cmꢀ1): 2952.03 (CH),
1736.90 and 649.05 (C@O), 1598.43, 1512.26 (C@C),
1261.28 (C–O). ESI-MS [M+1]:348.5; 1H NMR (DMSO-
d6, ppm): 7.68 (m, 2H), 7.44 (d, 1H, J = 15.6 Hz), 6.96 (m,
2H), 6.87 (d, 1H, J = 15.6 Hz), 5.33 (m, 1H), 4.44 (t, 1H,
J = 8.4 Hz), 3.95, 3.79 (m, 2H), 3.78 (s, 3H), 3.64 (s, 3H),
2.34, 2.16 (m, 2H), 2.02 (s, 3H).
5.1.14. (2S,4R,E)-Methyl 1-cinnamoyl-4-((E)-3-(4-meth-
oxyphenyl)acryloyloxy)-pyrrolidine-2-carboxylate. Pale
yellow powder, yield 59.8%, mp 121.1–122.8 °C. IR
(KBr, cmꢀ1): 2952.6 (CH), 1710.46 and 1653.34
(C@O), 1603.64 (C@C), 1161.94 (C–O). ESI-MS
1
[M+1]436.6; H NMR (DMSO-d6, ppm): 7.74 (m, 2H),
7.68 (m, 2H), 7.66 (d, 1H, J = 16.2 Hz), 7.51 (d, 1H,
J = 15 Hz), 7.41 (m, 3H), 7.05 (d, 1H, J = 15.6 Hz),
6.95 (m, 2H), 6.50 (d, 1H, J = 15.6 Hz), 5.49 (m, 1H),
4.53 (t, 1H, J = 7.8 Hz), 3.78 (m, 2H), 3.68 (s, 3H),
3.66 (s, 3H), 2.49, 2.23 (m, 2H).
5.1.15. (2S,4R,E)-Methyl 1-cinnamoyl-4-((E)-3-(3,4-
dimethoxyphenyl)acryloyloxy)-pyrrolidine-2-carboxylate
(A10).. White crystal, yield 56.3%, mp 136.6–137.5 °C. IR
(KBr, cmꢀ1): 2976.86 (CH), 1740.86 1711.44 (C@O),
1599.21, 1514.10 (C@C), 1248.84 (C–O). ESI-MS
[M+1]:466.6; 1H NMR (DMSO-d6, ppm): 7.75 (m, 2H),
7.63 (d, 1H, J = 15.6 Hz), 7.51 (d, 1H, J = 15.6 Hz),
7.38 (m, 4H), 7.25 (m, 1H), 7.07 (d, 1H, J = 15.6 Hz),
6.97 (d, 1H, J = 8.4 Hz), 6.58 (d, 1H, J = 16.2 Hz),
5.50 (m, 1H), 4.53 (t, 1H, J = 7.8 Hz), 4.08, 4.03 (m,
2H), 3.78 (s, 3H), 3.68 (s, 3H), 3.66 (s, 3H), 2.23, 1.98
(m, 2H).
5.2.4. Compounds B2, B3, B4, B5, and B7 were prepared
as described for compound B1
5.2.5. (2S,4R,E)-Methyl1-(3-(4-methoxyphenyl)acryloyl)-
4-(propionyloxy)pyrrolidine-2-carboxylate (B2). White
solid, yield 59.2%, mp 86–88 °C. IR (KBr, cmꢀ1):
2962.46 (CH), 1732.24 and 1652.0 (C@O), 1601.38 and
1513.86 (C@C), 1259.28 and 1175.32 (C–O). ESI-MS
[M+1]: 362.5. 1H NMR (DMSO-d6, ppm): 7.68 (m,
2H), 7.45 (d, 1H, J = 15.6 Hz), 6.97 (m, 2H), 6.87 (d,
1H, J = 15.6 Hz), 5.34 (m, 1H), 4.44 (t, 1H,
J = 8.4 Hz), 3.95, 3.94 (m, 2H), 3.79 (s, 3H), 3.64 (s,
3H), 2.50 (m, 1H), 2.34 (q, 2H, J = 2.4 Hz, 4.2 Hz),
2.16 (m, 1H), 1.00 (t, 3H, J = 7.2 Hz).
5.2. Compounds obtained from Scheme 1
5.2.1. (E) 4-Methoxyl cinnamoyl chloride (4). 4-methoxyl
cinnamic acid (17.8 g, 100 mmol) was dissolved in 40 ml
SOCl2 and120 ml benzene, and refluxed for 3 h. The
resulting solution rotary evaporated to get pale yellow
crystal.
5.2.6. (2S,4R,E)-methyl4-(butyryloxy)-1-(3-(4-methoxy-
phenyl)acryloyl)pyrrolidine-2-carboxylate (B3). White
solid, yield 63.8%, mp 54–56 °C. IR (KBr, cmꢀ1):
2962.38 (CH), 1731.99, 1652.09 (C@O), 1601.13,
1513.94 (C@C), 1259.49, 1175.19 (C–O). ESI-MS
[M+1]: 376.5. 1H NMR (DMSO-d6, ppm): 7.69 (m,
2H, Ar–H), 7.44 (d, 1H@CH, J = 15.6 Hz), 6.97 (m,
2H), 6.86 (d, 1H, J = 15.6 Hz), 5.35 (m, 1H), 4.44 (t,
1H, J = 7.8 Hz), 3.96 (m, 2H), 3.79 (s, 3H), 3.64 (s,
3H), 2.34, 2.15 (m, 2H), 2.28 (t, 2H, J = 7.2 Hz), 1.53
(m, 2H), 0.86 (t, 3H, J = 1.8 Hz).
5.2.2. (2S,4R,E)-Methyl 4-hydroxy-1-(3-(4-methoxyphe-
nyl)acryloyl)pyrrolidine-2-carboxylate (B0). Compound
1 (3.63 g, 20 mmol) was suspended in 50 ml Py and
5 ml Et3N. After stirred for 20 min at room temperature,
the resulting mixture was filtered. The filtrate was cooled
to ꢀ5 °C, and at this temperature 40 ml CH2Cl2 with
4.27 g 4 (24 mmol) was added. After stirred for 5 h,
the resulting mixture was filtrated to remove white pre-
cipitation, and the filtrate was rotary evaporated. Small
amount toluene was added to remove Py. The resulting
crude oil was dissolved with 200 ml CH2Cl2, washed
with 3 N HCl, H2O, saturated salt solution, and dried
over Na2SO4, anhydrous. The organic phase was rotary
evaporated to provide pale yellow crude product. The
crude solid was recrystallized with EtOAc-CHX (2:1)
to get 3.83 g of pale yellow lamellar crystal, yield
62.3%, mp139.4–140.6 °C. IR (KBr, cmꢀ1): 3197.98
(OH), 2952.18 (CH), 1731.41 and 1646.46 (C@O),
1573.98 and 1513.61 (C@C), 1255.35 (C–O). ESI-MS
[M+1]:306.5. 1H NMR (DMSO-d6, ppm): 7.68 (m,
2H), 7.43 (d, 1H, J = 15.6 Hz), 6.96 (m, 2H), 6.86 (d,
1H, J = 15.6 Hz), 5.22 (m, 1H), 4.42 (t, 1H,
J = 8.4 Hz), 4.40, 3.82 (m, 2H), 3.78 (s, 3H), 3.68 (s,
1H), 3.62 (s, 3H), 2.13, 1.92 (m, 2H).
5.2.7. (2S,4R,E)-Methyl4-(benzoyloxy)-1-(3-(4-methoxy-
phenyl)acryloyl)pyrrolidine-2-carboxylate (B4). White
crystal, yield 71.1%, mp 119.6–120.8 °C. IR (KBr,
cmꢀ1): 2958.74 (CH), 1731.86, 1649.15 (C@O),
1599.83, 1513.58 (C@C), 1262.25 (C–O). ESI-MS
[M+1]: 410.6. 1H NMR (DMSO-d6, ppm): 7.96 (m,
2H), 7.66 (m, 3H), 7.52 (m, 2H), 7.44 (d, 1H,
J = 15.6 Hz), 6.98 (m, 2H), 6.89 (d, 1H, J = 15.6 Hz),
5.61 (m, 1H), 4.58 (t, 1H, J = 8.4 Hz), 4.06, 4.04 (m,
2H), 3.78 (s, 3H), 3.66 (s, 3H), 2.29, 2.27 (m, 2H).
5.2.8. (2S,4R,E)-Methyl-4-(4-chlorobenzoyloxy)-1-(3-(4-
methoxyphenyl)acryloyl)pyrrolidine-2-carboxylate (B5).
White crystal, yield 69.5%, mp 108–110 °C. IR (KBr,
cmꢀ1): 2956.81 (CH), 1730.09 (C@O), 1600.74 and
1513.55 (C@C), 1264.97 (C–O). ESI-MS[M+1]:444.7;
1H NMR(DMSO-d6, ppm): 7.97 (m, 2H), 7.67 (m,

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L. Zhang et al. / Bioorg. Med. Chem. 14 (2006) 8286–8294
2H), 7.58 (m, 2H), 7.43 (d, 1H, J = 15.6 Hz), 6.95 (m,
2H), 6.88 (d, 1H, J = 15.6 Hz), 5.60 (m, 1H), 4.57 (t,
1H, J = 7.8 Hz), 4.14, 4.06 (m, 2H), 3.78 (s, 3H), 3.69
(s, 3H), 2.32, 2.26 (m, 2H).
4.51 (t, 1H, J = 8.4 Hz), 4.01, 3.99 (m, 2H), 3.81
(s, 3H), 3.78 (s, 3H), 3.68 (s, 3H), 2.43, 2.23 (m, 2H).
5.2.14. (2S,4R,E)-Methyl 4-((E)-3-(3,4-dimethoxyphe-
nyl)acryloyloxy)-1-((E)-3-(4-methoxyphenyl)acryloyl) py-
rrolidine-2-carboxylate(B10). White solid, yield 49.3%,
mp 141–143 °C. IR (KBr, cmꢀ1): 2938.5 (CH), 1744.4,
1645.77 (C@O), 1514.3 (C@O), 1140 (C–O). ESI-
5.2.9. (2S,4R,E)-Methyl1-(3-(4-methoxyphenyl)acryloyl)-
4-(3- phenylpropanoyloxy)pyrrolidine-2-carboxylate (B7).
Yellow solid, yield 54.4%, mp 61–64 °C. IR(KBr, cmꢀ1):
2952.5 (CH), 1739.5, 1651.3 (C@O), 1602.06, 1513.03
(C@C), 1250.3, 1174.55 (C–O). ESI-MS[M+1]: 438.6;
1H NMR(DMSO-d6, ppm): 7.48 (d, 1H, J = 15.6 Hz),
7.23 (m, 6H), 7.12 (m, 1H), 6.97 (m, 2H), 6.84 (d, 1H,
J = 15.6 Hz), 5.33 (m, 1H), 4.40 (t, 1H, J = 8.4 Hz),
3.94, 3.86 (m, 2H), 3.79 (s, 3H), 3.64 (s, 3H,), 2.83 (t,
2H, J = 7.2 Hz), 2.53 (t, 2H, J = 7.8 Hz), 2.14, 2.11 (m,
2H).
1
MS[M+1]:496.7; H NMR (DMSO-d6, ppm): 7.70 (m,
2H), 7.60 (d, 1H, J = 15.6 Hz), 7.46 (m, 1H), 7.37 (s,
1H), 7.25 (d, 1H, J = 7.8 Hz), 6.96 (m, 3H), 6.91 (d,
1H, J = 15.6 Hz), 6.58 (d, 1H, J = 16.6 Hz), 5.49 (m,
1H), 4.51 (t, 1H, J = 8.4 Hz), 4.05, 3.98 (m, 2H), 3.91
(s, 3H), 3.78 (s, 3H), 3.68 (s, 3H), 3.65 (s, 3H), 2.24,
2.21 (m, 2H).
5.3. Compounds getting from Scheme 1
5.2.10. (2S,4R,E)-Methyl-1-(3-(4-methoxyphenyl)acry-
loyl)-4-(3,4,5trimethoxy-benzoyloxy)pyrrolidine-2-carbo-
xylate (B6). Compound B0 (1.53 g, 5 mmol) was taken
in CH2Cl2 (20 ml) and Et3N (1.5 ml) was added at
0 °C. Five milliliters of CH2Cl2 with 3.6 g compound 3
was added dropwise and the resulting mixture was stir-
red for 4 h at room temperature. CH2Cl2 was added to
dilute the reaction mixture. The organic layer was
washed with 1 N HCl, H2O, saturated salt solution,
and dried over Na2SO4, anhydrous, filtered, and evapo-
rated to give pale yellow oil, which was chromato-
graphed over flash silica with chloroform-methanol
(50:1–30:1) to provide 1.6 g white powder, yield 64.2%,
mp 66–68 °C. IR(KBr, cmꢀ1): 2943.53 (CH), 1715.57
and 1651.85 (C@O), 1601.85 and 1513.13 (C@C),
1222.81, 1174.46 and 1127.7 (C–O). ESI-MS[M+1]:
5.3.1. (E)-3-(3,4-dimethoxyphenyl)-2-propenoic acid
(5)[108]. Caffeic acid (18 g, 0.1 mol) was dissolved in
cool 90 ml NaOH solution (4 mol/L), in which process
the inner temperature was required under 20 °C. After
Me2SO4 20 ml was added dropwise and stirred for
20 min, 50 ml NaOH solution (4 mol/L) and 20 ml
Me2SO4 were dropped into the reaction system con-
stantaneously. The inner temperature was required un-
der 35 °C. The resulting mixture was slowly heated to
90 °C in 1 h and maintained at this temperature for
1 h, and then the solution was refluxed for 1.5 h, after
50 ml NaOH solution (4 mol/L) was added, another
2 h of refluxing was applied. The pH of the resulting
solution was regulated to 2 by concentrated HCl.
Two to three hours later, mass brown solid was attained
by filtering, and wash to neutrality with water. The gross
was recrystallized in EtOH and H2O to get 16.4 g (yield
78.8%)light yellow crystal, mp179.4-181.1 °C, which
did not appear blue in Fe (SCN)3/FeCl3.
1
500.6. H NMR(DMSO-d6, ppm): 7.68 (m, 2H), 7.44
(d, 1H, J = 15.6 Hz), 7.24 (m, 2H), 6.96 (s, 1H), 6.94
(s, 1H), 6.89 (d, 1H, J = 15.6 Hz), 5.56 (m, 1H), 4.64
(t, 1H, J = 7.8 Hz), 4.09 (m, 2H), 3.81 (s, 3H), 3.78 (s,
6H), 3.72 (s, 3H), 3.67 (s, 3H), 2.51, 2.28 (m, 2H).
5.3.2. (E)-3-(3, 4-Dimethoxyphenyl)-2-acrolyl chloride
(6). Compound 5 (10.4 g, 50 mmol)was dissolved in
20 ml SOCl2 and 150 ml benzene, and refluxed for 3 h.
The resulting solution was rotary evaporated to get light
yellow crystal.
5.2.11. Compounds B8, B9, and B10 were prepared as
described for compound B6.
5.2.12.
(2S,4R)-Methyl4-(cinnamoyloxy)-1-((E)-3-(4-
methoxyphenyl)acryloyl)pyrrolidine-2-carboxylate (B8).
White needle crystal, yield 62.1%, mp 64.5–65.7 °C.
IR(KBr, cmꢀ1): 2952.15 (CH), 1712.15, 1650.98
(C@O), 1601.52, 1512.88 (C@C), 1250.25, 1173.37 (C–
5.3.3. (2S,4R,E)-Methyl 4-hydroxyl-1-(3-(3,4-dimethoxy-
phenyl)acryloyl)pyrrolidine-2-carboxylate (C0). Com-
pound 1 (1.82 g,10 mmol) was suspended in 20 ml Py
and 3 ml Et3N. After stirred for 20 min at room tem-
perature, the resulting mixture was filtered. The filtrate
was cooled to ꢀ5 °C, and at this temperature10 ml
CH2Cl2 with 2.82 g 6 (12 mmol) was added. After stir-
red for 4 h, the resulting mixture was filtered to remove
white precipitation, and the filtrate was rotary evapo-
rated. The resulting crude oil was chromatographed
over flash silica with petro ether/EtOAc (3:1–1:4) to
provide 2.4 g of pale yellow solid, yield 71.9%, mp
62.5–64.5 °C.
1
O). ESI-MS[M+1]: 436.7. H NMR (DMSO-d6, ppm):
7.74 (m, 2H), 7.70 (m, 2H), 7.68 (d, 1H, J = 15.6 Hz),
7.45 (d, 1H, J = 15.6 Hz), 7.41 (m, 3H), 6.98 (m, 2H),
6.92 (d, 1H, J = 15.6 Hz), 6.68 (d, 1H, J = 15.6 Hz),
5.50 (m, 1H), 4.52 (t, 1H, J = 8.4 Hz), 4.06, 4.01 (m,
2H), 3.78 (s, 3H), 3.66 (s, 3H), 2. 42, 2.24 (m, 2H).
5.2.13. (2S,4R)-Methyl 1-((E)-3-(4- methoxyphenyl)acry-
loyl)-4-((E)-3-(4-methoxyphenyl)acryloyloxy)pyrrolidine-
2-carboxylate(B9). Pale yellow powder, yield 55.6%, mp
61.2–63.4 °C. IR (KBr, cmꢀ1): 2953.09 (CH), 1709.24,
1651.24 (C@O), 1603.15, 1513.17 (C@C), 1251.38,
5.3.4. (2S,4R,E)-Methyl 4-acetoxy-1-(3-(3,4-dimethoxy-
phenyl)acryloyl)pyrrolidine-2-carboxylate (C1). In nitro-
gen atmosphere, compound C0 (3.35 g, 10 mmol) was
taken in CH2Cl2 (20 ml) and Et3N (4.5 ml) was added
at 0 °C. Five milliliters of CH2Cl2with 0.8 ml acetyl
1
1173.21 (C–O). ESI-MS[M+1]: 446.6; H NMR(DMSO-d6,
ppm): 7.68 (m, 4H), 7.63 (d, 1H, J = 15.6 Hz), 7.45 (d,
1H, J = 15.6 Hz), 6.97 (m, 4H), 6.91 (d, 1H,
J = 15.6 Hz), 6.52 (d, 1H, J = 15.6 Hz), 5.48 (m, 1H),

L. Zhang et al. / Bioorg. Med. Chem. 14 (2006) 8286–8294
8293
chloride was added dropwise and the resulting mixture
was stirred for 3 h at room temperature .CH2Cl2 was
added to dilute the reaction mixture. Then the organic
phase was washed with 1 N HCl, H2O, saturated salt
solution, dried over Na2SO4 anhydrous, filtered, and
evaporated to give pale yellow oil, which was chromato-
graphed over flash silica with petro ether-acetone (4:1–
1:2) to provide 2.8 g light yellow solid, yield 74.2%,
mp 45.6–47.6 °C. IR (KBr, cmꢀ1): 2953.3 (CH),
1746.2, 1603.3 (C@O), 1513.2 (C@C), 1262.7 (C–O).
ESI-MS[M+1]: 378.6. 1H NMR (DMSO-d6, ppm):
7.43 (d, 1H, J = 15 Hz), 7.37 (s, 1H), 7.21 (m, 1H),
6.96 (d, 1H, J = 8.4 Hz), 6.89 (d, 1H, J = 15.6 Hz),
5.34 (m, 1H), 4.44 (t, 1H, J = 8.4 Hz), 3.95 (m, 2H),
3.81 (s, 3H), 3.78 (s, 3H), 3.64 (s, 3H), 2.36, 2.15 (m,
2H), 2.02 (s, 3H).
6.90 (d, 1H, J = 15.6 Hz), 5.63 (m, 1H), 4.60 (t,1H,
J = 7.8 Hz), 4.13, 4.07 (m, 2H), 3.81 (s, 3H), 3.78 (s,
3H), 3.66 (s, 3H), 2.28, 1.98 (m, 2H).
5.3.10. (2S,4R,E)-Methyl-(-3-(3,4-dimethoxyphenyl)acry-
loyl)-4-(3- phenylpropanoyloxy)pyrrolidine-2-carboxylate
(C7). White needle crystal, yield 58.3%, mp 134.5–
135.5 °C. IR (KBr, cmꢀ1): 2948.6 (CH), 1739.95, 1650.0
(C@O), 1515.5, 1429.1 (C@C), 1265.2 (C–O). ESI-
1
MS[M+1]:468.4; H NMR (DMSO -d6, ppm): 7.42 (d,
1H, J = 15.6 Hz), 7.37 (s, 1H), 7.22 (m, 5H), 7.13 (m,
1H), 6.97 (d, 1H, J = 7.8 Hz), 6.86 (d, 1H, J = 15.6 Hz),
5.63 (m, 1H), 4.39 (t, 1H, J = 7.8 Hz), 4.07 (m, 2H), 3.82
(s, 3H), 3.79 (s, 3H), 3.66 (s, 3H), 2.82 (t, 2H,
J = 7.2 Hz), 2.6 (t, 2H, J = 7.2 Hz), 2.49, 1.98 (m, 2H).
5.3.11. Compounds C6, C8, C9, and C10 were prepared as
described for compound B6
5.3.5. Compounds C2, C3, C4, C5, and C7 were prepared
as described for compound C1
5.3.12.
(2S,4R,E)-Methyl1-(-3-(3,4-dimethoxyphenyl)
5.3.6.
(2S,4R,E)-Methyl1-(-3-(3,4-dimethoxyphenyl)
acryloyl-4-(3,4,5-trimethoxybenzonyloxy)pyrrolidine-2-
carboxylate (C6). White solid, yield 56.8%, mp 72–
74 °C. IR (KBr, cmꢀ1): 2942.65 (CH), 1715.33,
1651.25 (C@C), 1224.13 (C–O). ESI-MS[M+1]: 530.4;
1H NMR (DMSO-d6, ppm): 7.45 (d, 1H, J = 15.6 Hz),
7.36 (s, 1H), 7.24 (m, 2H), 7.16 (d, 1H, J = 4.8 Hz),
6.96 (d, 1H, J = 8.4 Hz), 6.90 (d, 1H, J = 15.6 Hz),
5.58 (m, 1H), 4.65 (t, 1H, J = 7.8 Hz), 4.10 (m, 2H),
3.82 (s, 3H), 3.81 (s, 6H), 3.78 (s, 3H), 3.72 (s, 3H),
3.67 (s, 3H), 2.58, 2.29 (m, 2H).
acryloyl)-4-propionyloxypyrrolidine-2-carboxylate (C2).
Light yellow solid, yield 64.3%, mp 62.6–63.8 °C. IR
(KBr, cmꢀ1): 2951.0 (CH), 1739.6, 1651.0 (C@O),
1
513.7 (C@C), 1266.3 (C–O). ESI-MS [M+1]: 392.3; H
NMR (DMSO-d6, ppm): 7.45 (d, 1H, J = 15.6 Hz),
7.36 (s, 1H), 7.22 (m, 1H), 6.98 (d, 1H, J = 8.4 Hz),
6.87 (d, 1H, J = 15.6 Hz), 5.36 (m, 1H), 4.46 (t, 1H,
J = 8.4 Hz), 3.97, 3.92 (m, 2H), 3.82 (s, 3H), 3.79 (s,
3H), 3.64 (s, 3H), 2.34 (q, 2H, J = 4.8 Hz, 3 Hz), 2.17,
1.98 (m, 2H), 1.01 (t, 3H, J = 7.8 Hz).
5.3.13.
(2S,4R)-Methyl4-cinnamoyloxy-1-((E)-3-(3,4-
5.3.7. (2S,4R,E)-Methyl 4-butyryloxy-1-(-3-(3,4-dimeth-
oxyphenyl)acryloyl)pyrrolidine-2-carboxylate
dimethoxyphenyl)acryloyl)pyrrolidine-2-carboxylate (C8).
Pale yellow solid, yield 54.7%, mp 59.6–61.5 °C. IR
(KBr, cmꢀ1): 2952.9 (CH), 1746.4, 1711.8, 1650 (C@O),
(C3).
White solid, yield 57.6%, mp 46.5–47.7 °C. IR (KBr,
cmꢀ1): 2961.9 (CH), 1738.9 and 1650.9 (C@O), 1513.7
(C@C), 1266.0 (C@O). ESI-MS[M+1]: 406.6; 1H
NMR (DMSO-d6, ppm): 7.43 (d, 1H, J = 15.6 Hz),
7.37 (s, 1H), 7.23 (m, 1H), 6.97 (d, 1H, J = 7.8 Hz),
6.88 (d, 1H, J = 15 Hz), 5.36 (m, 1H), 4.44 (t, 1H,
J = 7.8 Hz), 3.96 (m, 2H), 3.81 (s, 3H), 3.78 (s, 3H),
3.64 (s, 3H), 2.34 (m, 1H)2.29 (t, 2H, J = 4.8 Hz), 2.15
(m, 1H), 1.52 (m, 2H), 0.86 (t, 2H, J = 7.8 Hz).
1
1514.0 (C@C), 1162.3 (C–O). ESI-MS [M+1]: 466.5; H
NMR (DMSO-d6, ppm): 7.73 (m, 3H, Ar–H), 7.42 (m,
5H), 7.22 (m, 1H), 6.96 (d, 1H, J = 8.4 Hz), 6.91 (d, 1H,
J = 15.6 Hz), 6.68 (d, 1H, J = 15.6 Hz), 5.51 (m, 1H),
4.53 (t, 1H, J = 7.8 Hz), 4.04 (m, 2H), 3.81 (s, 3H), 3.78
(s, 3H), 3.66 (s, 3H), 2.49, 2.25 (m, 2H).
5.3.14. (2S,4R)-Methyl1-((E)-3-(3,4-dimethoxyphenyl)
acryloyl)-4-((E)-3-(4-methoxy-phenyl)acryloyloxy)
pyrrolidine-2-carboxylate (C9). Light yellow solid, yield
55.6%, mp 52.6–53.8 °C. IR (KBr, cmꢀ1): 2953.7 (CH),
1741.1, 1650.5 (C@O), 1598.5, 1513.8 (C@C), 1266.1
(C–O). ESI-MS [M+1]:496.8; 1H NMR (DMSO-d6,
ppm): 6.75 (m, 3H), 6.50 (d, 1H, J = 15.6 Hz), 6.40 (d,
1H, J = 15.6 Hz), 6.16 (m, 4H), 6.04 (d, 1H,
J = 15.6 Hz), 5.61 (d, 1H, J = 15.6 Hz), 5.59 (m, 1H),
3.87 (t, 1H, J = 7.8 Hz), 3.31, 3.29 (m, 2H), 3.08 (s, 3H),
3.06 (s, 3H), 3.02 (s, 3H), 2.97 (s, 3H), 1.75, 1.51 (m, 2H).
5.3.8. (2S,4R,E)-Methyl 4-benzoyloxy-1-(-3-(3,4-dimeth-
(C4).
oxyphenyl)acryloyl)pyrrolidine-2-carboxylate
White crystal, yield 66.2%, mp 72.4–73.6 °C.IR (KBr,
cmꢀ1): 2952.56 (CH), 1719.8 and 1650.6 (C@O), 1513.3
1
(C@C), 1268.8 (C–O). ESI-MS[M+1]: 440.6. H NMR
(DMSO-d6, ppm): 7.97 (m, 2H), 7.65 (m, 1H), 7.51 (m,
2H), 7.43 (d, 1H, J = 15.6 Hz), 7.36 (s, 1H), 7.18 (m,
1H), 6.95 (m, 1H), 6.89 (d, 1H, J = 14.4 Hz), 5.63 (m,
1H), 4.60 (t, 1H, J = 7.8 Hz), 4.11, 4.07 (m, 2H), 3.81 (s,
3H), 3.78 (s, 3H), 3.67 (s, 3H), 2.50, 2.30 (m, 2H).
5.3.15. (2S,4R,E)-Methyl1-((E)-3-(3,4-dimethoxyphenyl)
acryloyl)-4-((E)-3-(3,4-dime-thoxyphenyl)acryloyloxy)
pyrrolidine-2-carboxylate (C10). Pale yellow solid, yield
52.8%, mp 75.5–77.4 °C. IR (KBr, cmꢀ1): 2938.5 (CH),
1744.4 and 1645.77 (C@O), 1514.3 (C@O), 1140 (C–
5.3.9. (2S,4R,E)-Methyl 4-(chlorobenzoyloxy)-1-(-3-(3,
4-dimethoxyphenyol)acryloyl)pyrrolidine-2-carboxylate
(C5). White needle crystal, yield 63.2%, mp 65.0–
67.1 °C. IR (KBr, cmꢀ1): 2952.64 (CH), 1722.17,
1650.89 (C@O), 1513.26 (C@C), 1269.02 (C–O).
ESI-MS[M+1]: 474.4. 1H NMR (DMSO-d6, ppm):
7.98 (m, 2H), 7.60 (m, 2H), 7.43 (d, 1H, J = 15.6 Hz),
7.35 (s, 1H), 7.22 (m, 1H), 6.97 (d, 1H, J = 8.4 Hz),
1
O). ESI-MS [M+1]: 526.6. H NMR (DMSO-d6, ppm):
7.63 (d, 1H, J = 15.6 Hz), 7.44 (d, 1H, J = 15 Hz), 7.37
(m, 2H), 7.24 (m, 2H), 6.97 (m, 2H), 6.92 (d, 1H,
J = 15.6 Hz), 6.58 (d, 1H, J = 16.2 Hz), 5.51 (m, 1H),

8294
L. Zhang et al. / Bioorg. Med. Chem. 14 (2006) 8286–8294
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Acknowledgment
This work was supported by the Doctoral Science Foun-
dation of the Ministry of Education of China (Grant
No. 20020422024).
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