Y.-Z. Xu et al. / European Journal of Medicinal Chemistry 94 (2015) 284e297
295
d
d
d
d
5.76 (2H, m),
4.81 (1H, s),
3.62 (4H, t, J ¼ 6.4 Hz),
d
5.57 (1H, d, J ¼ 3.2 Hz),
4.13 (1H, d, J ¼ 8.8 Hz),
3.26 (1H, m),
2.82 (1H, dd, J ¼ 8.8, 2.8 Hz),
2.25 (4H, m),
1.43 (1H, m); 13C NMR (400 MHz, CDCl3)
172.8, 169.9, 152.5, 146.9, 144.4, 138.9, 129.5, 121.2, 117.1, 114.4,
d
5.42 (1H, s),
d
d
4.98 (1H, s),
3.71 (4H, t, J ¼ 6.8 Hz),
2.89 (2H, t, J ¼ 8.0 Hz),
2.54 (1H,
d
5.78 (2H, m),
4.98 (1H, s),
3.61 (4H, t, J ¼ 6.8 Hz),
J ¼ 8.8, 2.8 Hz), 2.56 (3H, m), 2.36 (4H, m),
(2H, t, J ¼ 7.6 Hz),
1.44 (1H, m); 13C NMR (400 MHz, CDCl3)
d
5.56 (1H, d, J ¼ 3.2 Hz),
d
5.47 (1H, d, J ¼ 0.8 Hz),
d
d
d
4.83 (1H, s),
d
4.14 (1H, d, J ¼ 8.8 Hz),
d 3.69 (4H, t,
d
d
J ¼ 6.8 Hz),
d
d
3.26 (1H, m),
d
2.83 (1H, dd,
1.92
173.4,
d
2.64 (2H, t, J ¼ 8.0 Hz),
d
d
d
d
2.21 (2H, m), d
m),
d
d
d
d
d
169.9, 152.6, 146.8, 144.2, 138.8, 130.3, 129.6, 121.3, 116.9, 114.4,
112.0, 86.0, 80.0, 75.3, 53.5, 53.3, 40.4, 40.0, 37.4, 35.7, 33.8, 33.7,
31.2, 26.7; MS (ESI) m/z: 548.3 (M þ Hþ).
112.2, 85.9, 80.1, 75.4, 53.6, 53.4, 40.4, 40.1, 37.4, 36.1, 35.6, 31.9,
30.9; MS (ESI) m/z: 534.3 (M þ Hþ).
4.1.2.8. 3
4(15),10(14),11(13)-triene-5
Light yellow oil, 22.3 mg (40.5%); 1H NMR (400 MHz, CDCl3)
a
-oxo-p-[N,N-bis(2-chloroethyl)amino]hydrocinnamoyl-
,7 -dihydroxyl-6 ,12-guaianolide (4e).
7.09
6.24 (1H, d, J ¼ 3.2 Hz),
5.48 (1H, d, J ¼ 1.6 Hz),
4.09 (1H, d, J ¼ 8.8 Hz), 3.69 (4H, t,
3.61 (4H, J ¼ 6.4 Hz), 3.45 (1H, m), 2.86 (3H, m),
2.62 (2H, t, J ¼ 7.6 Hz), 2.20 (2H,
2.00 (1H, dd, J ¼ 15.2, 6.4 Hz),
1.41 (1H, m); 13C NMR
172.9, 169.8, 150.7, 148.7, 144.6, 139.0, 129.6,
4.1.2.13. 3
4(15),10(14),11(13)-triene-5
Light yellow oil, 21.7 mg (38.4%); 1H NMR (400 MHz, CDCl3)
a
-oxo-p-[N,N-bis(2-chloroethyl)amino]butyryl-
,7 -dihydroxyl-6 ,12-guaianolide(5e).
7.07
6.25 (1H, d, J ¼ 3.6 Hz),
5.12 (1H, s), 4.98 (1H, s),
3.70 (4H, t, J ¼ 6.8 Hz), 3.63 (4H,
2.89 (1H, m),
2.79 (1H, dd, J ¼ 14.8,
2.56 (2H, t, J ¼ 7.2 Hz), 2.35 (2H, t, J ¼ 7.2 Hz), 2.23 (2H,
2.08 (1H, dd, J ¼ 14.8, 6.4 Hz), 1.92 (2H, t, J ¼ 7.6 Hz), 1.41
(1H, m); 13C NMR (400 MHz, CDCl3)
173.3, 169.8, 151.0, 148.6,
a
a
a
a
a
a
d
d
(2H, d, J ¼ 8.4 Hz),
d
6.62 (2H, d, J ¼ 8.8 Hz),
5.81 (1H, d, J ¼ 1.6 Hz), 5.55 (2H, m),
5.10 (1H, s), 4.95 (1H, s),
d
(2H, d, J ¼ 8.8 Hz),
d
6.63 (2H, d, J ¼ 8.4 Hz),
5.87 (1H, d, J ¼ 2.0 Hz), 5.56 (3H, m),
4.12 (1H, d, J ¼ 8.8 Hz),
3.47 (1H, m) d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
J ¼ 6.8 Hz),
d
d
d
J ¼ 6.4 Hz),
8.0 Hz),
m),
d
d
d
2.74 (1H, dd, J ¼ 16.0, 8.4 Hz),
d
d
d
d
d
m),
d
d
d
d
d
(400 MHz, CDCl3)
d
d
129.1, 121.2, 119.3, 115.7, 112.1, 84.9, 81.9, 78.3, 72.0, 53.5, 44.9, 40.5,
144.2, 138.9, 129.7, 121.3, 119.3, 115.7, 112.3, 85.0, 81.9, 78.2, 71.8,
53.6, 45.0, 40.3, 38.2, 33.9, 33.7, 31.3, 30.6, 26.7; MS (ESI) m/z: 564.1
(M þ Hþ).
38.2, 36.1, 31.3, 30.5, 29.9; MS (ESI) m/z: 550.1 (M þ Hþ).
4.1.2.9. 14-oxo-p-[N,N-bis(2-chloroethyl)amino]hydro-
cinnamoylmelampolide(4f). Light yellow oil, 29.2 mg (56.2%); 1H
4.1.2.14. 14-oxo-p-[N,N-bis(2-chloroethyl)amino]butyr-
NMR (400 MHz, CDCl3)
J ¼ 7.6 Hz), 6.16 (1H, d, J ¼ 3.2 Hz),
(1H, d, J ¼ 3.2 Hz), 4.99 (1H, d, J ¼ 10.0 Hz),
4.57 (1H, t, J ¼ 9.6 Hz), 4.42 (1H, d, J ¼ 12.4 Hz),
3.60 (4H, t, J ¼ 7.2 Hz), 2.86 (2H, t,
2.58 (2H, t, J ¼ 7.6 Hz), 2.54 (1H, m), 2.15 (4H, m),
1.83 (3H, d, J ¼ 0.8 Hz),
1.50 (1H, m); 13C NMR
172.5, 170.1, 144.3, 139.8, 138.1, 135.8, 129.6,
d
7.13 (2H, d, J ¼ 8.4 Hz),
5.49 (1H, t, J ¼ 8.0 Hz),
4.64 (1H, d,
d
6.79 (2H, d,
ylmelampolide(5f). Light yellow oil, 23.4 mg (43.7%); 1H NMR
d
d
d
5.39
(400 MHz CDCl3)
d
7.06 (2H, d, J ¼ 8.4 Hz),
5.54 (1H, t, J ¼ 8.4 Hz),
5.08 (1H, d, J ¼ 10.0 Hz),
4.45 (1H, d, J ¼ 12.0 Hz),
3.61 (4H, t, J ¼ 6.4 Hz), 2.59 (1H, m),
2.33 (2H, t, J ¼ 7.2 Hz), 2.20 (4H, m),
1.85 (3H, d, J ¼ 1.2 Hz),
1.55 (1H, m); 13
173.2, 170.2, 144.3, 139.8, 138.2, 135.9,
d
6.63 (2H, d, J ¼ 8.8 Hz),
d
d
d
6.17 (1H, d, J ¼ 3.6 Hz),
d
d
5.41 (1H, d,
J ¼ 12.4 Hz),
d
d
J ¼ 2.8 Hz),
d
d
4.64 (1H, d, J ¼ 11.6 Hz),
d
3.74 (4H, t, J ¼ 7.2 Hz),
d
d
d
4.59 (1H, t, J ¼ 9.6 Hz),
d
d
d
3.71 (4H, t,
2.54 (2H, t,
J ¼ 7.6 Hz),
d
d
d
J ¼ 6.4 Hz),
J ¼ 7.2 Hz),
d
d
d
2.01 (3H, m),
d
d
d
d
d 2.08 (3H, m),
(400 MHz, CDCl3)
d
d
1.89 (2H, t, J ¼ 7.6 Hz),
d
d
C
129.3, 125.2, 118.7, 112.3, 112.2, 80.4, 67.3, 53.4, 45.1, 40.4, 38.0, 35.9,
NMR (400 MHz, CDCl3)
d
29.7, 25.0, 24.8, 23.9, 17.0; MS (ESI) m/z: 520.2 (M þ Hþ).
130.3, 129.8, 129.6, 125.3, 118.8, 112.1, 80.5, 67.3, 53.5, 45.3, 40.5,
38.1, 33.9, 33.6, 26.7, 25.2, 24.9, 24.1, 17.1; MS (ESI) m/z: 556.1
(M þ Naþ).
4.1.2.10. 15-oxo-m-[N,N-bis(2-chloroethyl)amino]hydrocinnamoyl-
14-oxo-cis,cis-germacranolide(4g). Light yellow oil, 21.0 mg (39.3%);
1H NMR (400 MHz, CDCl3)
d
9.39 (1H, d, J ¼ 0.8 Hz),
6.63 (2H, d, J ¼ 8.8 Hz), 6.52 (1H, t, J ¼ 6.8 Hz),
5.60 (1H, d, J ¼ 2.4 Hz), 5.42 (1H, d, J ¼ 9.6 Hz),
4.50 (1H,
d
7.10 (2H, d,
4.1.2.15. 15-oxo-m-[N,N-bis(2-chloroethyl)amino]butyryl-14-oxo-
J ¼ 8.8 Hz),
d
d
d
6.28
cis,cis-germacranolide(5g). Light yellow oil, 25.2 mg (45.9%); 1H
(1H, d, J ¼ 2.8 Hz),
d
d
NMR (400 MHz, CDCl3)
d
9.40 (1H, s),
6.55 (1H, t, J ¼ 8.0 Hz),
5.52 (1H, d, J ¼ 9.2 Hz),
4.54 (1H, d, J ¼ 13.2 Hz), 4.46 (1H, d, J ¼ 13.6 Hz),
3.62 (4H, t, J ¼ 6.0 Hz), 2.85 (1H, m),
2.55 (4H, m), 2.48 (3H, m), 2.30 (3H, m), 1.92
1.69 (1H, m); 13C NMR (400 MHz, CDCl3)
195.1,
d
7.07 (2H, d, J ¼ 8.8 Hz),
6.28 (1H, d, J ¼ 2.4 Hz),
5.06 (1H, dd,
d 6.65
d
5.05 (1H, dd, J ¼ 9.6, 4.0 Hz),
d
4.54 (1H, d, J ¼ 13.6 Hz),
d
(2H, d, J ¼ 8.4 Hz),
d
d
d, J ¼ 14.4 Hz),
d
3.70 (4H, t, J ¼ 6.4 Hz),
d
3.61 (4H, t, J ¼ 6.4 Hz),
2.64 (2H, t, J ¼ 7.6 Hz),
d
5.60 (1H, d, J ¼ 2.0 Hz),
d
d
d
d
2.87 (2H, t, J ¼ 7.6 Hz),
d
2.76 (2H, m),
d
J ¼ 9.2, 4.0 Hz),
d
d
2.50 (5H, m),
d
2.28 (1H, m),
d
1.67 (1H, m); 13C NMR (400 MHz,
d
d
3.70 (4H, t, J ¼ 6.8 Hz),
d
d
CDCl3)
d
195.2, 172.5, 169.7, 152.5, 144.5, 143.7, 138.7, 134.7, 129.5,
2.75 (1H, m),
d
d
d
d
129.3, 129.2, 123.3, 112.3, 77.3, 66.8, 53.5, 43.3, 40.0, 35.9, 31.5, 29.7,
(2H, t, J ¼ 7.2 Hz),
d
d
26.0, 25.1, 22.1; MS (ESI) m/z: 534.2 (M þ Hþ).
173.0.5, 169.7, 152.3, 144.4, 143.7, 138.6, 134.7, 130.2, 129.6, 128.9,
123.3, 112.1, 77.6, 66.5, 53.5, 43.3, 40.5, 33.8, 33.4, 31.5, 26.6, 26.1,
25.2, 22.1; MS (ESI) m/z: 548.1 (M þ Hþ).
4.1.2.11. 3
4(15),10(14),11(13)-triene-6
20.4 mg (38.2%); 1H NMR (400 MHz, CDCl3)
J ¼ 8.4 Hz), 6.63 (2H, d, J ¼ 8.8 Hz), 6.24 (1H, d, J ¼ 3.2 Hz),
(1H, t, J ¼ 6.0 Hz), 5.55 (1H, s), 5.51 (1H, d, J ¼ 3.2 Hz), 5.40 (1H,
s), 4.95 (1H, s), 4.81 (1H, s), 3.70 (4H, t,
3.91 (1H, t, J ¼ 9.2 Hz),
J ¼ 6.8 Hz), 3.61 (4H, t, J ¼ 6.4 Hz), 3.07 (2H, m), 2.87 (1H, m),
2.56 (3H, m), 2.30 (4H, m), 2.12 (1H, m), 1.91 (3H, m), 1.40
(1H, m); 13C NMR (400 MHz, CDCl3)
173.2, 169.9, 149.0, 147.9,
a
-oxo-p-[N,N-bis(2-chloroethyl)amino]phenylbutyryl-
,12-guaianolide (5c). Light yellow oil;
7.07 (2H, d,
5.69
a
d
4.1.3. General procedure for the synthesis of compounds 2d0 and 2e0
To a well stirred solution of d and e (0.05 mmol) in dry DCM
(3 mL) was added 2 (1.2 equive) and PPh3 (2.5 quive), followed by
the addition dropwise of the solution of DEAD (2.5 epuive) at rt
with the reaction being monitored by TLC analysis (petroleum
ether/ethyl acetate 2:1). Then water was added and the mixture
was extracted with DCM. The combined organic extract was dried
over anhydrous MgSO4 and concentrated in vacuo. The crude res-
idue was purified by column chromatography on silica gel (eluant,
petroleum ether/ethyl acetate).
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
144.2, 139.1, 130.4, 129.6, 120.5, 115.4, 113.4, 112.0, 85.0, 75.8, 53.5,
49.7, 45.1, 44.5, 40.4, 37.2, 36.7, 33.8, 30.9, 26.7; MS (ESI) m/z: 532.2
(M þ Hþ).
4.1.2.12. 3
4(15),10(14),11(13)-triene-5
Colorless oil; 29.6 mg (53.9%); 1H NMR (400 MHz, CDCl3)
d, J ¼ 8.4 Hz), 6.63 (2H, d, J ¼ 8.4 Hz),
a
-oxo-p-[N,N-bis(2-chloroethyl)amino]phenylbutyryl-
4.1.3.1. 3
4(15),10(14),11(13)-triene-5
Light yellow oil; 12.8vmg (50.6%); 1H NMR (400 MHz, CDCl3)
(2H, d, J ¼ 8.8 Hz), 6.69 (2H, d, J ¼ 9.2 Hz), 6.28 (1H, d, J ¼ 3.6 Hz),
b
-oxo-p-[N,N-bis(2-chloroethyl)amino]benzoyl-
a
-hydroxyl-6
a
,12-guaianolide
(5d).
a
-hydroxyl-6
a
,12-guaianolide(2d0).
d
7.07 (2H,
d 7.97
d
d
6.27 (1H, d, J ¼ 3.2 Hz),
d
d