Synthesis and anti-tumor activity of novel ethyl 3-aryl-4-oxo-3,3a,4,6- tetrahydro-1H-furo[3,4-c]pyran-3a-carboxylates

Article abstract of DOI:10.1016/j.bmcl.2011.04.003

A series of ethyl 3-aryl-4-oxo-3,3a,4,6-tetrahydro-1H-furo[3,4-c]pyran-3a- carboxylates were prepared through the metal-catalyzed domino reaction of alkylidene malonates and 1,4-butynediol under a one-pot reaction condition at room temperature. Their in vitro anti-proliferative activities were subsequently evaluated in A549, QGY and HeLa cells. The majority of the compounds showed potent anti-tumor activity against HeLa cells. In particular, compound 3l was the most potent compound with IC₅₀ value of 5.4 μM. For the first time, the X-ray structure of the anti-tumor ethyl 3-aryl-4-oxo-3,3a,4,6- tetrahydro-1H-furo[3,4-c]pyran-3a-carboxylates is determined.

Full text of DOI:10.1016/j.bmcl.2011.04.003

Bioorganic & Medicinal Chemistry Letters 21 (2011) 3381–3383
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and anti-tumor activity of novel ethyl 3-aryl-4-oxo-3,3a,4,6-tetra-
hydro-1H-furo[3,4-c]pyran-3a-carboxylates
Tiantian Wang a, Jia Liu a, Hanyu Zhong a, Huan Chen a, Zhiliang Lv a, Yikai Zhang a, Mingfeng Zhang a,
a,
Dongping Geng a, Chunjuan Niu a, Yongmei Li b, , Ke Li
⇑
⇑
a Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, PR China
b Department of Oncology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of ethyl 3-aryl-4-oxo-3,3a,4,6-tetrahydro-1H-furo[3,4-c]pyran-3a-carboxylates were prepared
through the metal-catalyzed domino reaction of alkylidene malonates and 1,4-butynediol under a one-
pot reaction condition at room temperature. Their in vitro anti-proliferative activities were subsequently
evaluated in A549, QGY and HeLa cells. The majority of the compounds showed potent anti-tumor activ-
ity against HeLa cells. In particular, compound 3l was the most potent compound with IC50 value of
Received 3 December 2010
Revised 26 March 2011
Accepted 1 April 2011
Available online 7 April 2011
5.4
lM. For the first time, the X-ray structure of the anti-tumor ethyl 3-aryl-4-oxo-3,3a,4,6-tetrahydro-
Keywords:
Anti-tumor
Domino reaction
1H-furo[3,4-c]pyran-3a-carboxylates is determined.
Ó 2011 Elsevier Ltd. All rights reserved.
Crystal structure
Ethyl 4-oxo-3,3a,4,6-tetrahydro-1H-
furo[3,4-c]pyran-3a-carboxylate
Cancer is the second leading cause of death worldwide and ac-
counted for 7.6 million deaths in 2008 (WHO Fact sheet No. 297,
February 2011). Consequently, various categories of anticancer
drugs have been developed, such as: paclitaxe,1 doxorubicin2 and
vinblastine3 that have been used clinically for the treatment of
breast, lung, stomach, prostate, colon, or pancreatic tumor or other
solid tumors. However, undesirable side effects and extensive mul-
ti-drug resistance in cancer cells has been a major obstacle to suc-
cessful cancer chemotherapy.4 Hence, there is a pressing need for
developing novel compounds that are able to overcome these
obstacles while maintaining anti-cancer potency by preventing
cancer cell proliferation.
O
O
CO2Et
CO2Et
a
b
CHO
1
CO2Et
R
R
R
O
2
3
Scheme 1. Reagents and conditions: (a) CH2(CO2C2H5)2/piperidine/HOAc, toluene,
reflux, 10–16 h, 70–82%; (b) 1,4-butynediol/NaH/CuI, THF, rt, 43–80%.
catalyzed domino reaction condition. The in vitro anti-proliferative
activities in various cancer cell lines were also evaluated.
Recently, domino reactions have been of great interest because
of their capacity to generate molecular diversity within a mini-
mum number of steps.5 Among these reactions, metal-catalyzed
[3+2] cycloaddition reaction is a particularly efficient approach,
especially in the synthesis of five- and six-membered heterocy-
cles.6 We are interested in applying alkylidene malonates to the
synthesis of oxygen-containing heterocycles, and part of our re-
search is focused on the reaction between 1,4-butynediol and
alkylidene malonates. Herein we report an efficient and straight-
forward method for the syntheses of ethyl 3-aryl-4-oxo-3,3a,
4,6-tetrahydro-1H-furo[3,4-c]pyran-3a-carboxylate through the
reaction of 1,4-butynediol with alkylidene malonates under Cu-
The ethyl 3-aryl-4-oxo-3,3a,4,6-tetrahydro-1H-furo[3,4-c]pyr-
an-3a-carboxylates were synthesized according to Scheme 1 with
43–80% yield. With piperidine and glacial acetic acid as catalyst,
the reaction of appropriate aryl formaldehydes 1 with diethyl mal-
onate under refluxing condition afforded alkylidene malonates7 2.
Compound 2 (1 equiv) was reacted with 1,4-butynediol (1.5 equiv)
in the presence of NaH (0.6 equiv) and CuI (0.1 equiv) at room tem-
perature in THF, within 6 h, product 3 was obtained with 43–80%
yield.8 With an electron-withdrawing group or an electron-donat-
ing group on the aryl ring or heteroaromatic substitution being ap-
plied, the reaction could be performed smoothly. Nevertheless, an
electron-withdrawing group on the aryl ring was slightly more fa-
vored than an electron-donating group. Furthermore, it should be
noted that para-substituents help to form ethyl 3-aryl-4-oxo-3,
3a,4,6-tetrahydro-1H-furo[3,4-c]pyran-3a-carboxylate, especially
⇑
Corresponding authors. Tel.: +86 21 81871237 (Y.L.).
E-mail addresses: proflike@sina.com (Y. Li), liyongmei1976@sina.com (K. Li).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.04.003

3382
T. Wang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3381–3383
Table 1
evaluated in three human tumor cell lines: A549 (lung carcinoma),
Synthesis
of
ethyl
3-aryl-4-oxo-3,3a,4,6-tetrahydro-1H-furo[3,4-c]pyran-3a-
QGY (hepatoma) and HeLa (cervical carcinoma). All the compounds
were assessed with quintuplicate dose-response assays indicated
by certain growth parameters (colorimetric MTT assay) for their
in vitro cytotoxic activities against the three human tumor cell
lines. Dose–response curves were created by plotting cytotoxic ef-
fect against the log10 of the drug concentration for each cell line.
Cytotoxic effects of each compound were determined by IC50 val-
ues, which represent the molar of drug concentration required to
cause 50% growth inhibition. The biological screening results of
carboxylatesa
Entry
3
Substrate R
NaH
(equiv)
Temp
(°C)
Time
(h)
Yieldb
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
Ph
2-F-Ph
4-F-Ph
3-Cl-Ph
4-Cl-Ph
3,4-Cl2-Ph
4-Br-Ph
4-t-Bu-Ph
4-OCH3-Ph
3,4-(OCH3)2-Ph
3,5-(OCH3)2-Ph
3,4,5-(OCH3)3-Ph
4-N(CH3)2-Ph
4-NO2-Ph
2-Furanyl
2-Thienyl
2-Pyridyl
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
20
20
20
20
20
20
20
20
25
25
25
30
25
20
20
20
20
6
6
6
3
6
3
6
6
6
6
6
6
6
6
6
6
3
62
64
72
43
77
47
59
51
70
56
53
52
49
80
66
54
57
ethyl
3-aryl-4-oxo-3,3a,4,6-tetrahydro-1H-furo[3,4-c]pyran-3a-
carboxylate with 5-fluorouracil as a control for their anti-prolifer-
ative activities are summarized in Table 2.
As shown in Table 2, the majority of newly synthesized com-
pounds exhibited compound-specific potency against the HeLa
cells. All these compounds possess
a common ethyl 4-oxo-
3,3a,4,6-tetrahydro-1H-furo[3,4-c]pyran-3a-carboxylate nucleus
in which substitution at C-3 positions plays important roles in
determining potency of ethyl 3-aryl-4-oxo-3,3a,4,6-tetrahydro-
1H-furo[3,4-c]pyran-3a-carboxylates. Introduction of electron-
donating moieties aryl ring (3i–3l) at C-3 position enhanced
the anti-proliferative activity, and furthermore, multi-electron-
donating substitution of aromatic ring at C-3 position displays
higher anti-proliferative activity than single-electron-donating
substitution of aryl ring at C-3 position. For instance, 3,4,5-trime-
thoxyphenyl substitution (3l) at C-3 position showed the best
a
Unless otherwise specified, the reaction was carried on 20.0 mmol scale in
50 mL of solvent.
b
Isolated yield.
when the para-substituent was NO2 or Cl. By that means, the
reaction could easily produce pure compound 3 with high yield
(Table 1, entries 5 and 14).
anti-proliferative activity (IC50 = 5.4 lM), that is much more effec-
tive than 4-methoxy-phenyl substitution at C-3 position. The com-
All the synthesized compounds were structurally characterized
by 1H NMR, 13C NMR and mass spectral analysis.9,10 For the first
time, the X-ray crystallographic structure of ethyl 3-(3,5-dime-
thoxyphenyl)-4-oxo-3,3a,4,6-tetrahydro-1H-furo[3,4-c]pyran-3a-
carboxylates (3k), a representative compound of the series of
ethyl 3-aryl-4-oxo-3,3a,4,6-tetrahydro-1H-furo[3,4-c]pyran-3a-
carboxylates with anti-tumor activity, is determined. The ORTEP
III view of the molecule ethyl 3-(3,5-dimethoxyphenyl)-4-oxo-
3,3a,4,6-tetrahydro-1H-furo[3,4-c]pyran-3a-carboxylate (3k) is
shown in Figure 1 (CCDC 756985). It is worth noticing that
although there are two chiral centers in the molecule of compound
3k, only a pair of enantiomers was observed in X-ray single crystal.
The C7 is a tertiary carbon which configuration was determined by
the configuration of C3 during the formation of the rings. While the
3,3a-dihydro-1H-furo[3,4-c]pyran-4(6H)-one ring almost lies in
one plane, the 3,5-dimethoxyphenyl and the ethyl carboxylate
groups that link to C3 and C7, respectively, adopt an extended
conformation.
pound (3l) also showed moderate anti-tumor activity against A549
cells (13.3 lM). However, introduction of an electron-withdrawing
or a larger group substitution aromatic ring at C-3 position slightly
decreased the activity. For instance, the compounds of 4-nitro-
phenyl (3n) and 4-tert-butyl-phenyl (3h) substitution at C-3 posi-
tion only exhibited moderate activities, with IC50 of 53.4 and
23.4 lM, respectively. Furthermore, introduction of halo atom at
C-3 aryl ring is detrimental to the activity (3d–3g), whereas
replacement of 4-chlorophenyl (3e) or 4-bromophenyl (3g) group
at C-3 position with 4-fluorophenyl yielded a compound (3c) with
significant improved anti-tumor activity against HeLa cells. In
addition, heteroaryl substitutions of 3o–3q at C-3 position retained
in vitro anti-tumor activity against HeLa cells. Lastly, all the ethyl
Table 2
Cytotoxic activities of ethyl 3-aryl-4-oxo-3,3a,4,6-tetrahydro-1H-furo[3,4-c]pyran-
3a-carboxylatesa (IC50 M)b
, l
No.
Compound
HeLa
A549
QGY
The anti-tumor activities of ethyl 3-aryl-4-oxo-3,3a,4,6-tetrahy-
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
5-FU
12.8
22.1
22.9
>103
117.5
72.4
48.7
25.4
18.3
10.0
16.0
5.4
23.4
53.4
28.3
30.4
20.7
16.1
>103
>103
>103
28.4
>103
>103
>103
>103
9.3
>103
>103
>103
>103
>103
>103
>103
>103
>103
>103
>103
>103
>103
>103
>103
>103
>103
14.1
dro-1H-furo[3,4-c]pyran-3a-carboxylates
were
subsequently
>103
>103
13.3
89.6
36.8
>103
>103
>103
5.6
a
The cytotoxicity (as IC50 for each cell line) is the concentration of compound
that reduced the optical density of treated cells by 50% with respect to untreated
cells using the MTT assay.
b
Data represent the mean values of three independent determinations.
Figure 1. X-ray crystal structures of compound 3k (CCDC 756985).

T. Wang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3381–3383
3383
7. For selected examples see: (a) Cavicchioli, M.; Sixdenier, E., et al Tetrahedron
Lett. 1997, 38, 1763; (b) Marat, X.; Monteiro, N.; Balme, G. Synlett 1997, 845; (c)
Clique, B.; Monteiro, N.; Balme, G. Tetrahedron Lett. 1999, 40, 1301; (d)
Monteiro, N.; Balme, G. J. Org. Chem. 2000, 65, 3223; (e) Bottex, M.; Cavicchioli,
M., et al J. Org. Chem. 2001, 66, 175; (f) Nakamura, M.; Liang, C., et al Org. Lett.
2004, 6, 2015; (g) Gowrisankau, A.; Park, D. Y.; Kim, J. N. Bull. Korean Chem. Soc.
2005, 26, 1826; (h) Morikawa, S.; Yamazaki, S., et al J. Org. Chem. 2006, 71,
3540; (i) Morikawa, S.; Yamazaki, S., et al J. Org. Chem. 2007, 72, 6459.
8. (a) Bigi, F.; Carloni, S.; Ferrari, L.; Maggi, R.; Mazaccani, A.; Sartori, G.
Tetrahedron Lett. 2001, 42, 5203; (b) Cardillo, G.; Fabbroni, S.; Gentilucci, L.;
Gianotti, M.; Tolomelli, A. Synth. Commun. 2003, 33, 1587.
9. General experimental procedure for synthesis of ethyl 3-aryl-4-oxo-3,3a,4,6-
tetrahydro-1H-furo[3,4-c]pyran-3a-carboxylates: NaH (60% in mineral oil,
12 mmol) was added to a solution of but-2-yne-1,4-diol (30 mmol) in THF
(50 mL) under nitrogen, and the solution was stirred for 5 min at room
temperature. alkylidene malonate (2, 20 mmol) and CuI (2 mmol) were then
added successively. When plenty of target compound were observed by TLC,
the reaction mixture was quenched by dropwise addition of a 20% solution of
HCl, immediately cooled to room temperature. The mixture was further diluted
and extracted twice with CH2Cl2, and the organics washed successively with
saturated solution of brine, and water. The organic extracts were dried over
MgSO4, filtered, concentrated, and the residue purified by flash column
chromatography to afford compound 3.
3-aryl-4-oxo-3,3a,4,6-tetrahydro-1H-furo[3,4-c]pyran-3a-carbox-
ylates didn’t show anti-proliferative activity in QGY cells. Never-
theless, some of these compounds (3d, 3i, 3l, 3m and 3n)
demonstrated moderate anti-proliferative activities in inhibiting
A549 cell growth with IC50 at a micromolar range between 9.3
and 89.6 lM. Among these compounds, 3i (IC50 = 9.3 lM) was
the most potent one with anti-proliferative activity equivalent to
the control drug 5-FU in A549 cells.
In conclusion, we have developed a simple one-pot synthesis of
novel ethyl 3-aryl-4-oxo-3,3a,4,6-tetrahydro-1H-furo[3,4-c]pyran-
3a-carboxylates and evaluated their anticancer activities in three
human cancer cell lines. Most of the compounds showed potent
anti-proliferative activities in HeLa cells. While a few of them
showed moderate anti-proliferative activities in A549 cells. In par-
ticular, the compounds 3l and 3i were found to be the most potent
compounds in HeLa and A549 cells, with IC50 values of 5.4 and
9.3 lM, respectively. Our ongoing experiments are being carried
out to identify their cellular targets and to improve the potency
and the selectivity of this series of compounds.
10. Selected data for compounds 3a–q: Compound 3a: White solid; mp: 59.7–
60.4 °C. IR: 3462, 3068, 3033, 2977, 2931, 2862, 1728, 1495, 1458, 1386, 1313,
1232, 1185, 1088, 1056, 1022, 985, 958, 921, 862, 806, 754, 700 cmÀ1 1H NMR
.
(CDCl3, 300 MHz): d 7.69–7.72 (m, 1H), 7.27–7.37 (m, 1H), 6.06–6.08 (m, 1H),
5.48 (s, 1H), 4.95 (d, J = 13.8 Hz, 1 H), 4.83–4.86 (m, 2H), 4.62 (d, J = 13.8 Hz,
1H), 3.73 (q, J = 6.9 Hz, 2H), 0.81 (t, J = 6.9 Hz, 3H) ppm. 13C NMR (CDCl3,
75 MHz): d 167.42, 164.77, 141.64, 136.24, 127.98, 127.67, 126.77, 115.61,
83.91, 68.64, 67.52, 64.17, 62.06, 53.36, 13.28 ppm. ESIMS: m/s (%):311.81
[M+Na]+. Anal. Calcd for C16H16O5: C, 66.66; H, 5.59. Found: C, 66.53; H, 5.65.
Compound 3c: white solid; mp: 107.3–107.9 °C. IR: 3466, 3114, 3076, 3021,
2984, 2936, 2914, 2878, 2858, 2030, 1915, 1752, 1724, 1604, 1508, 1459, 1447,
1413, 1382, 1367, 1346, 1301, 1233, 1186, 1158, 1102, 1070, 1056, 1015, 982,
Acknowledgment
Financial support form the National Natural Science Foundation
of China (No. 30572238), the Chinese Academy of Sciences.
Supplementary data
965, 922, 868, 854, 835, 819, 803, 786, 739, 712 cmÀ1 1H NMR (CDCl3,
.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.04.003.
300 MHz): d 7.68–7.73 (m, 2H), 7.00–7.05 (m, 2H), 6.05–6.08 (m, 1H), 5.42 (s,
1H), 4.96 (d, J = 13.8 Hz, 1 H), 4.83–4.85 (m, 2H), 4.63 (d, J = 13.8 Hz, 1 H), 3.80
(q, J = 7.2 Hz, 2H), 0.87 (t, J = 7.2 Hz, 3H) ppm. 13C NMR (CDCl3, 75 MHz): d
167.45, 164.75, 164.20, 160.93, 141.61, 132.01, 128.75, 128.74, 115.75, 114.74,
83.44, 68.68, 67.63, 64.09, 62.25, 13.46 ppm. ESIMS: m/s (%): 329.76 [M+Na]+.
References and notes
Anal. Calcd for
C16H15FO5: C, 62.74; H, 4.94. Found: C, 62.57; H, 4.77.
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Compound 3i: white solid, mp: 95.4–95.9 °C. IR: 3462, 3435, 3074, 3007,
2986, 2964, 2937, 2917, 2860, 2840, 2360, 2045, 1940, 1908, 1723, 1610, 1583,
1511, 1452, 1421, 1386, 1358, 1303, 1246, 1175, 1112, 1083, 1032, 983, 967,
921, 852, 837, 816, 797, 775, 74 cmÀ1 1H NMR (CDCl3, 300 MHz): d 7.61(d,
.
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J = 9.0 Hz, 2H), 6.86(d, J = 9.0 Hz, 2H), 6.02–6.06 (m, 1H), 5.40(s, 1H), 4.95 (d,
J = 11.7 Hz, 1 H), 4.81–4.84 (m, 2H), 4.61(d, J = 11.7 Hz, 1 H), 3.78–3.85 (m, 5H),
0.9(t, J = 7.2 Hz, 3H) ppm; 13C NMR (CDCl3, 77 MHz): d 167.51, 164.94, 159.45,
141.98, 128.18, 115.55, 113.16, 83.93, 68.59, 67.56, 64.17, 62.16, 55.15,
13.51 ppm. ESIMS: m/s (%): 351.7 [M+Na]+. Anal. Calcd for C17H18O6: C,
64.14; H, 5.70. Found: C, 54.33; H, 5.67. Compound 3l. white solid; mp: 124.4–
124.8 °C. IR: 3432, 3078, 2998, 2961, 2936, 2870, 2838, 1751, 1722, 1592,
1508, 1463, 1421, 1385, 1359, 1328, 1235, 1215, 1188, 1127, 1081, 1062, 1006,
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(s, 2H), 6.07 (m, 1H), 5.40 (s, 1H), 4.99 (d, J = 13.8 Hz, 1H), 4.83–4.85 (m, 2H),
4.65 (d, J = 13.8 Hz, 1H), 3.80–3.87 (m, 11H), 0.88 (t, J = 6.9 Hz, 3H) ppm; 13C
NMR (CDCl3, 75 MHz):
d 167.60, 164.87, 153.73, 141.96, 137.58, 131.83,
115.69, 103.95, 83.91, 68.76, 67.61, 64.32, 62.25, 60.75, 56.10, 13.56 ppm.
ESIMS: m/s (%): 379.45 [M+H]+. Anal. Calcd for C19H22O8: C, 60.31; H, 5.86.
Found: C, 60.41; H, 5.89%. Compound 3q: red oil, IR: 3442, 3087, 3057, 2974,
2928, 2862, 1728, 1458, 1386, 1369, 1323, 1184, 1058, 1025, 984, 958, 921,
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T. H.; Ullah, E.; Lahiri, S.; Gorls, H.; Langer, P. J. Org. Chem. 2004, 69, 9128.
857, 806, 763, 713 cmÀ1 1H NMR (CDCl3, 300 MHz): d 8.62(s, 1H), 7.69–7.80
.
(m, 2H), 7.30 (s, 1H), 6.05 (d, J = 2.7 Hz, 1H), 5.45 (s, 1H), 4.92 (d, J = 10.5 Hz,
1H), 4.74–4.82 (m, 2H), 4.63 (d, J = 15.0 Hz, 1H), 3.82 (q, J = 7.2 Hz, 2H), 0.81 (t,
J = 7.2 Hz, 3H) ppm. 13C NMR (CDCl3, 75 MHz): d 166.86, 164.41, 154.90,
147.12, 139.65, 138.17, 122.82, 116.17, 83.39, 69.16, 67.78, 62.81, 62.25,
13.28 ppm. ESIMS: m/s (%): 312.17 [M+Na]+. Anal. Calcd for C15H15NO5: C,
62.28; H, 5.23; N, 4.84. Found: C, 62.42; H, 5.37; N, 4.77.