Synthesis of norcantharidin-dimer derivatives

Article abstract of DOI:10.1002/jhet.483

We use one molecule of ethylene diamine as a connecting arm to combine two molecules of 5,6-dehydronorcantharidin. Then, ten novel norcantharidin derivatives were synthesized in a single step by the [3 + 2] 1,3-dipolar cycloaddition reaction with oxime or hydrazone in the presence of chloramine-T, which is simpler than the conventional method.

Full text of DOI:10.1002/jhet.483

158
Synthesis of Norcantharidin-dimer Derivatives
Liping Deng,a,b* Zhang Yong,a Weifeng Tao,b
Vol 48
Jianfeng Shen,c and Wei Wangb
aDepartment of Pharmacology, Chemistry and Chemical Engineering Institute, Shaoxing
University, Shaoxing, Zhejiang 312000, People’s Republic of China
bZhejiang Supor Pharmaceuticals, Shaoxing, Zhejiang 312000, People’s Republic of China
cZhejiang Zhenyuan Pharmaceuticals, Shaoxing, Zhejiang 312000, People’s Republic of China
*E-mail: wwdlp@126.com
Received February 2, 2010
DOI 10.1002/jhet.483
Published online 6 October 2010 in Wiley Online Library (wileyonlinelibrary.com).
We use one molecule of ethylene diamine as a connecting arm to combine two molecules of 5,6-
dehydronorcantharidin. Then, ten novel norcantharidin derivatives were synthesized in a single step by
the [3 þ 2] 1,3-dipolar cycloaddition reaction with oxime or hydrazone in the presence of chloramine-
T, which is simpler than the conventional method.
J. Heterocyclic Chem., 48, 158 (2011).
INTRODUCTION
adenocystic carcinoma, neuroblastoma, bone, leukaemia,
ovarian, and colon cancer cell lines [5]. We have
recently referred to all the known Cantharidin SAR
data, briefly, no modification of the bicyclo [2.2.1] skel-
eton is permissible, the 7-oxa bridge are required to
maintain activity, the presence of double bond (5,6-ene)
has little effect on activity [6–10].
Cantharidin (CAN,exo,exo-2,3-dimethyl-7-oxabicyclo
[2.2.1] heptane-2,3-dicarboxylic acid anhydride, Fig. 1)
is an active ingredient of Chinese blister beetles Mylab-
ris [1], which has been used in China as a medicinal
agent for the treatment of cancer, in particular to hepa-
toma [2]. Recently, cantharidin has been found active in
cervical, tongue, ginival, bone, leukaemia, ovarian, and
colon cancer cells [3]. However, the renal toxicity of
this drug has limited its application [4]. Norcantharidin
(NCTD, the demethylated cantharidin derivative, Fig. 1)
appeared to improve the awkward side of cantharidin,
making the drug safer in application. It was recently
found to be capable of inducing apoptosis in human
cervical, tongue, ginival, mucoepidermoid carcinoma,
Isoxazoline and pyrazoline derivatives possess a wide
range of pharmacological activities [11]. Thus, it seemed
of interest to combine isoxazoline or pyrazoline with
norcantharidin derivatives in a single molecule. We
have successfully synthesized some compounds before
[12], but the method is somewhat complex, because we
have to synthesize nitrile oxide by the reaction of nitrile
oximes with tert-butyl hypochloride. With our sustained
interest in the synthesis of norcantharidin derivatives,
C
V
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January 2011
Synthesis of Norcantharidin-dimer Derivatives
159
mmol) was added. The reaction mixture was refluxed in DMF
for 9 h, and then leached. The extracts were poured into ice
water (50 mL), separating out crystal, then leached. The resi-
due was dried then recrystallized from methanol to give the
compound 3.
General procedure for the preparation of the 5,6-dehy-
dronorcantharidin-isoxazoline and 5,6-dehydronorcanthari-
din-pyrazoline adducts (4a–4e and 5a–5e). Chloramine-T
(2.4 mmol) was added to a solution of 2 (1 mmol) and 4-fluo-
robenzaldehyde oxime (2 mmol) in ethanol (20 mL). The reac-
tion mixture was refluxed in ethanol for 14 h, and then
leached. The residue was dried then recrystallized from metha-
nol to give the compound 4a.
The synthesis of compounds 4b–4e and 5a–5e were per-
formed using the same method.
Data.
(1R,2S,3R,4S)-3-(2-((1R,3R,4S)-3-carboxy-7-oxabicyclo [2.2.1]hept-
5-enecarboxamido)ethylcarbamoyl)-7-oxabicyclo[2.2.1]hept-5-
ene-2-carboxylic acid (2). This compound was obtained as
beige crystals, yield 67.5%, m.p. 97ꢀC; 1H NMR(DMSO-d6)
Figure 1. Chemical structures of CAN, NCTD, and chloramine-T.
we have achieved a facile 1,3-dipolar cycloaddition
method by using chloramine-T (Fig. 1). Chloramine-T,
which is a versatile reagent in organic synthesis [13],
was used in this article for the in situ oxidation of
oximes and hydrazones of aldehydes to generate the
nitrile oxides; compared with the conventional method,
the synthetic route is more facile, and the reaction rate
is enhanced tremendously.
In addition, the dimer may have a character or func-
tion, which is not possessed in a single state. Therefore,
we use ethylenediamine as a connecting arm to synthe-
size norcantharidin-dimer derivatives. Cooperating with
isoxazole or pyrazole, we look forward to the com-
pounds obtained having a good biological activity.
0
d: 08.07 (s, 2H, NAH), 5.71 (s, 4H, C5AH, C5 AH, C6AH,
0
C6 AH), 4.77 (s, 2H, C1AH, C1 AH), 4.59 (s, 2H, C4AH,
C4 AH), 3.47 (s, 4H, (CH2)2), 3.17 (s, 2H, C3AH, C3 AH),
3.01 (s, 2H, C2AH, C2 AH). Anal. Calcd. for C18H20N2O8: C,
0
0
0
55.10; H, 5.14; N, 7.14. Found: C, 55.12; H, 5.17; N, 7.13.
2,20-(Ethane-1,2-diyl)bis[4,7-epoxy-3a,4,7,7a-tetrahydro-1H-
isoindole-1,3(2H)-dione] (3). This compound was obtained as
beige crystals, yield 25.5%, m.p. 219ꢀC; 1H NMR(DMSO-d6)
0
0
RESULTS AND DISCUSSION
d: 5.65 (s, 4H, C5AH, C5 AH, C6AH, C6 AH), 4.71 (s, 4H,
0
0
C1AH, C1 AH, C4AH, C4 AH), 3.709 (s, 4H, (CH2)2), 3.11 (s,
The synthetic route of the compounds mentioned are
outlined in Scheme 1. Such type of compounds (Table
1) with versatile activities may be of interest in chemis-
try, biochemistry, and pharmacology [14].
0
4H, C2AH, C2 AH, C3AH, C3 AH). Anal. Calcd. for
Scheme 1
EXPERIMENTAL
Melting points were obtained on a B-540 Bu†chi melting
point apparatus and were uncorrected. 1H NMR spectra were
recorded on a Brucker AM-400 M Hz spectrometer with
SiMe4 as the internal standard in CDCl3. Element analyses
were performed on an EA-1110 instrument.
Nitrile oxides are of great synthetic interest because the
product, isoxazolines and pyrazolines, are versatile intermedi-
ates for the synthesis of bifunctional compounds. We have car-
ried out the [4 þ 2] cycloaddition of furan with maleic anhy-
dride to obtain 5,6-dehydronorcantharin 1. And then, we use
one molecule of ethylene diamine as a connecting arm to com-
bine two molecules of 5,6-dehydronorcantharidin, giving com-
pound 2. After that, we reacted compound 2 with DCC to get
compound 3. At last, we carried out the [3 þ 2] cycloaddition
of 3 with oxime or hydrazone in the presence of chloramine-T.
Thus, we get compounds 4a–4e and 5a–5e [12,15].
General procedure for the preparation of the compound
2. Ethylene diamine (10 mmol) was slowly added to a solution
of compound 1 (20 mmol) in acetone (30 mL). The reaction
mixture was refluxed in acetone for 8 h, and then leached. The
residue was dried, giving the compound 2.
General procedure for the preparation of the compound
3. Compound 2 (5 mmol) dissolved in DMF (15 mL), being
ice-bath. When the solution was down to 0ꢀC, DCC (10
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

160
L. Deng, Z. Yong, W. Tao, J. Shen, and W. Wang
Vol 48
Table 1
Physical data of compounds.
Analysis (%) calcd./found
Compound
R1/R2
/
Time (h)
8
m.p. (ꢀC)
97
Yield (%)
67.5
Molecular formula
C18H20N2O8
C
H
N
2
55.10
55.12
60.67
60.65
60.95
60.94
57.93
57.89
46.64
46.66
59.47
59.50
59.83
59.82
70.96
70.94
64.95
64.99
59.88
59.85
67.92
67.91
65.60
65.63
5.14
5.17
4.53
4.55
3.84
3.87
3.65
3.66
3.91
3.93
4.40
4.41
3.84
3.87
4.87
4.88
4.21
4.23
3.65
3.67
4.27
4.29
4.36
4.34
7.14
7.13
3
/
9
219
>300
>300
187
25.5
37.4
51.8
25.1
5.3
C18H16N2O6
C32H24N4O8F2
C32H24N4O8Cl2
C22H22N4O10S2
C34H30N4O12
C34H26N4O12
C44H36N6O6
7.86
7.87
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
C6H4F
22.5
22.5
21
8.89
8.91
8.44
8.42
9.89
9.97
8.16
8.14
C6H4Cl
C6H4SOCH3
C6H3OCH3OH
C7H5O2
C6H5
21.5
23
217
184
19.0
21.6
18.2
28.8
27.4
11.7
8.21
8.20
21
207
11.28
11.26
10.33
10.28
9.52
C6H4Cl
20
>300
>300
191
C44H34N6O6Cl2
C44H32N6O6Cl4
C48H36N10O6
C48H38N12O6
C6H3Cl2
C8H5N2
C8H6N3
22
9.54
23
16.50
16.53
19.12
19.11
22.5
203
0
C18H16N2O6: C, 60.67; H, 4.53; N, 7.86. Found: C, 60.65; H,
4.55; N, 7.87.
(s, 2H, C1AH, C1 AH), 4.52 (d, J ¼ 7.90 Hz, 2H, C6AH,
0
0
C6 AH), 3.59 (d, J ¼ 7.91 Hz, 2H, C3AH, C3 AH), 3.77 (s,
6,60-(Ethane-1,2-diyl)bis[exo,exo-4,8-epoxy-3a,4,4a,7a,8,8a-
hexahydro-3-(4-fluorophenyl)-pyrrolo[3,4-f]-1,2-benzisoxazole-
5,7(1H,3aH)-dione] (4a). This compound was obtained as
4H, (CH2)2), 3.38 (d, J ¼ 7.92 Hz, 2H, C2AH, C2 AH),
0
3.27(s, 6H, 2SOCH3). Anal. Calcd. for C22H22N4O10S2: C,
46.64; H, 3.91; N, 9.89. Found: C, 46.66; H, 3.93; N, 9.87.
6,60-(Ethane-1,2-diyl)bis[exo,exo-4,8-epoxy-3a,4,4a,7a,8,8a-
hexahydro-3-(3-hydroxy-4-methoxyphenyl)-pyrrolo[3,4-f]-1,2-
benzisoxazole-5,7(1H,3aH)-dione] (4d). This compound was
obtained as beige crystals, yield 5.3%, m.p. 217ꢀC; 1H
NMR(CDCl3) d: 8.37–7.49 (m, 6H, Ar-H), 5.25 (d, J ¼ 7.90
1
beige crystals, yield 37.4%, m.p. >300ꢀC; H NMR(CDCl3) d:
7.83–7.25(m, 8H, Ar-H), 5.23 (d, J ¼ 7.92 Hz, 2H, C5AH,
0
0
0
C5 AH), 4.98 (s, 2H, C4AH, C4 AH), 4.76 0 (s, 2H, C1AH,
C1 AH), 4.51 (d, J ¼ 7.90 Hz, 2H, C6AH, C6 AH), 3.59 (d, J
0
¼ 7.91 Hz, 2H, C3AH, C3 AH), 3.74 (s, 4H, (CH2)2), 3.38 (d,
0
0
0
J
¼
7.90 Hz, 2H, C2AH, C2 AH). Anal. Calcd. for
C32H24N4O8F2: C, 60.95; H, 3.84; N, 8.89. Found: C, 60.94;
Hz, 2H, C5AH, C5 AH), 5.02 (s, 2H, C4AH, C4 AH), 4.80
0
(s, 2H, C1AH, C1 AH), 4.53 (d, J ¼ 7.92 Hz, 2H, C6AH,
0
0
H, 3.87; N, 8.91.
C6 AH), 3.66 (d, J ¼ 7.91 Hz, 2H, C3AH, C3 AH), 3.83
(s, 6H, 2OCH3), 3.74 (s, 4H, (CH2)2), 3.44 (d, J ¼ 7.91 Hz,
6,60-(Ethane-1,2-diyl)bis[exo,exo-4,8-epoxy-3a,4,4a,7a,8,8a-
hexahydro-3-(4-chlorophenyl)-pyrrolo[3,4-f]-1,2-benzisoxazole-
5,7(1H,3aH)-dione] (4b). This compound was obtained as
0
2H, C2AH, C2 AH). Anal. Calcd. for C34H30N4O12: C, 59.47;
H, 4.40; N, 8.16. Found: C, 59.50; H, 4.41; N, 8.14.
1
beige crystals, yield 51.8%, m.p. >300ꢀC; H NMR(CDCl3) d:
6,60-(Ethane-1,2-diyl)bis[exo,exo-4,8-epoxy-3a,4,4a,7a,8,8a-
hexahydro-3-(benzo[d][1,3]dioxol-5-yl)-pyrrolo[3,4-f]-1,2-ben-
zisoxazole-5,7(1H,3aH)-dione] (4e). This compound was
obtained as beige crystals, yield 19.0%, m.p. 184ꢀC; 1H
NMR(CDCl3) d: 7.91–7.33 (m, 6H, Ar-H), 6.07 (s, 4H,
7.74–7.06(m, 8H, Ar-H), 5.18 (d, J ¼ 7.91 Hz, 2H, C5AH,
0
0
0
C5 AH), 4.95 (s, 2H, C4AH, C4 AH), 4.73 0 (s, 2H, C1AH,
C1 AH), 4.48 (d, J ¼ 7.92 Hz, 2H, C6AH, C6 AH), 3.59 (d, J
0
¼ 7.91 Hz, 2H, C3AH, C3 AH), 3.75 (s, 4H, (CH2)2), 3.36 (d,
0
0
J
¼
7.90 Hz, 2H, C2AH, C2 AH). Anal. Calcd. for
C32H24N4O8Cl2: C, 57.93; H, 3.65; N, 8.44. Found: C, 57.89;
2OCH2O), 5.27 (d, J ¼ 7.90 Hz, 2H, C5AH, C5 AH), 5.12
0
0
(s, 2H, C4AH, C4 AH), 4.81 (s, 2H, C1AH, C1 AH), 4.51 (d, J
0
H, 3.66; N, 8.42.
6,60-(Ethane-1,2-diyl)bis[exo,exo-4,8-epoxy-3a,4,4a,7a,8,8a-
hexahydro-3-(4-(methylsulfinyl)phenyl)-pyrrolo[3,4-f]-1,2-benzi-
¼ 7.90 Hz, 2H, C6AH, C6 AH), 3.56 (d, J ¼ 7.91 Hz, 2H,
0
C3AH, C3 AH), 3.73 (s, 4H, (CH2)2), 3.41 (d, J ¼ 7.90 Hz,
0
2H, C2AH, C2 AH). Anal. Calcd. for C34H26N4O12: C, 59.83;
soxazole-5,7(1H,3aH)-dione] (4c). This
compound was
H, 3.84; N, 8.21. Found: C, 59.82; H, 3.87; N, 8.20.
obtained as beige crystals, yield 25.1%, m.p. 187ꢀC; 1H
6,60-(Ethane-1,2-diyl)bis[rel-(3aR,4S,4aR,7aS,8S,8aR)-4,8-
epoxy-1,3-diphenyl-4,4a,6,7a,8,8a-hexahydropyrrolo[3,4-f]inda-
zole-5,7(1H,3aH)-dione] (5a). This compound was obtained as
NMR(CDCl3) d: 7.83–7.20(m, 8H, Ar-H), 5.24 (d, J ¼ 7.90
0
0
Hz, 2H, C5AH, C5 AH), 4.98 (s, 2H, C4AH, C4 AH), 4.75
Journal of Heterocyclic Chemistry
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Synthesis of Norcantharidin-dimer Derivatives
161
beige crystals, yield 21.6%, m.p. 207ꢀC; 1H NMR(CDCl3)
6,60-(Ethane-1,2-diyl)bis[rel-(3aR,4S,4aR,7aS,8S,8aR)-4,8-ep-
oxy-1-phenyl-3-(2-phenyl-2H-1,2,3-triazol-4-yl)-4,4a,6,7a,8,8a-hex-
ahydropyrrolo[3,4-f]indazole-5,7(1H,3aH)-dione] (5e). This com-
pound was obtained as beige crystals, yield 11.7%, m.p. 203ꢀC;
1H NMR(CDCl3) d: 8.53 (s, 2H, 2HAC¼¼N), 8.20–6.93 (m,
0
d: 7.77–6.91 (m, 20H, Ar-H), 5.33 (s, 2H, C4AH, C4 AH),
0
5.27 (s, 2H, C1AH, C1 AH), 4.66–4.64 (d, J ¼ 9.60 Hz,
0
2H, C5AH, C5 AH), 4.16–4.14 (d,
J
¼
9.60 Hz, 2H,
0
C6AH, C6 AH), 3.74 (s, 4H, (CH2)2), 3.39–3.37 (d, J ¼
0
0
7.20 Hz, 2H, C3AH, C3 AH), 3.34–3.32 (d, J ¼ 7.20 Hz,
20H, Ar-H), 5.51 (s, 2H, C4AH, C4 AH), 5.34 (s, 02H, C1AH,
0
0
2H, C2AH, C2 AH). Anal. Calcd. for C44H36N6O6: C,
70.96; H, 4.87; N, 11.28. Found: C, 70.94; H, 4.88; N,
C1 AH), 4.65–4.62 (d, J ¼ 9.60 Hz, 2H, C5AH, C5 AH), 4.21–
0
4.18 (d, J ¼ 9.60 Hz, 2H, C6AH, C6 AH), 3.75 (s, 4H, (CH2)2),
0
11.26.
3.41A3.39 (d, J ¼ 7.20 Hz, 2H, C3AH, C3 AH), 3.30–3.28 (d, J
6,60-(Ethane-1,2-diyl)bis[rel-(3aR,4S,4aR,7aS,8S,8aR)-4,8-
epoxy-1-phenyl-3-(2-chlorophenyl)-4,4a,6,7a,8,8a-hexahydropyr-
rolo[3,4-f]indazole-5,7(1H,3aH)-dione] (5b). This compound
0
¼ 7.20 Hz, 2H, C2AH, C2 AH). Anal. Calcd. for C48H38N12O6:
C, 65.60; H, 4.36; N, 19.12 Found: C, 65.63; H, 4.34; N, 19.11.
1
was obtained as beige crystals, yield 18.2%, m.p. >300ꢀC; H
REFERENCES AND NOTES
NMR(CDCl3) d: 7.81–6.96 (m, 18H, Ar-H), 5.31 (s, 2H,
0
0
0
C4AH, C4 AH), 5.01 (s, 02H, C1AH, C1 AH), 4.65 (s, 4H,
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C5AH, C5 AH, C6AH, C6 AH), 3.704 (s, 4H, (CH2)2), 3.30 (s,
0
4H, C2AH, C2 AH, C3AH, C3 AH). Anal. Calcd. for
C44H34N6O6Cl2: C, 64.95; H, 4.21; N, 10.33. Found: C, 64.99;
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H, 4.23; N, 10.28.
6,60-(Ethane-1,2-diyl)bis[rel-(3aR,4S,4aR,7aS,8S,8aR)-4,8-
epoxy-1-phenyl-3-(2,3-dichlorophenyl)-4,4a,6,7a,8,8a-hexahydro-
pyrrolo[3,4-f]indazole-5,7(1H,3aH)-dione] (5c). This compound
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1
was obtained as beige crystals, yield 28.8%, m.p. >300ꢀC; H
NMR(CDCl3) d: 7.65–6.94 (m, 16H, Ar-H), 5.31 (s, 2H,
0
0
C4AH, C4 AH), 5.00 (s, 2H, C1AH, C1 AH), 4.67–4.65 (m,
0
0
4H, C5AH, C5 AH, C6AH, C6 AH), 3.75 (s, 4H, (CH2)2),
0
0
[8] Hart, M. E.; Chamberlin, A. R.; Walkom, C.; Sakoff, J. A.;
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3.31–3.29 (m, 4H, C2AH, C2 AH, C3AH, C3 AH). Anal.
Calcd. for C44H32N6O6Cl4: C, 59.88; H, 3.65; N, 9.52. Found:
C, 59.85; H, 3.67; N, 9.54.
6,60-(Ethane-1,2-diyl)bis[rel-(3aR,4S,4aR,7aS,8S,8aR)-4,8-
epoxy-1-phenyl-3-(quinoxalin-2-yl)-4,4a,6,7a,8,8a-hexahydropyr-
rolo[3,4-f]indazole-5,7(1H,3aH)-dione] (5d). This compound
was obtained as beige crystals, yield 27.4%, m.p. 191ꢀC; 1H
NMR(CDCl3) d: 9.54 (s, 2H, 2HAC¼¼N), 8.14–7.00 (m, 18H,
[12] Deng, L. P.; Liu, F.-M.; Wang, H.-Y. J Heterocycl Chem
2005, 42, 13.
0
Ar0-H), 5.58 (s, 2H, C4AH, C4 AH), 5.38 (s, 2H, C1AH,
0
C1 AH), 4.70–4.68 (d, J ¼ 9.20 Hz, 2H, C5AH, C5 AH),
[13] Padmavathi, V.; Venugopal, R. K.; Padmaja, A.; Venugopa-
lan, P. J Org Chem 2003, 68, 1567.
0
4.26–4.24 (d, J ¼ 9.20 Hz, 2H, C6AH, C6 AH), 3.76 (s, 4H,
0
(CH2)2), 3.49–3.47 (d, J ¼ 7.20 Hz, 2H, C3AH, C3 AH),
[14] Deng, L. P.; Yang, B.; He, Q. J.; Hu, Y. Z. Lett Drug Des
Discov 2008, 5, 225.
0
3.38–3.36 (d, J ¼ 7.20 Hz, 2H, C2AH, C2 AH). Anal. Calcd.
for C48H36N10O6: C, 67.92; H, 4.27; N, 16.50. Found: C,
67.91; H, 4.29; N, 16.53.
[15] Liu, F.-L.; Jiang, T.; Zuo, D.-S.; Qi, X.; Zhan, X.-L. Chin J
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet