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P. Teng et al. / European Journal of Medicinal Chemistry 50 (2012) 63e74
2.51e2.87 (m, 4H), 2.50 (d, J ¼ 15.9 Hz, 1H), 2.46 (s, 3H), 2.78 (t,
J ¼ 7.5 Hz, 1H), 2.17 (td, J ¼ 12.0, 2.4 Hz, 1H), 1.92 (td, J ¼ 12.6, 4.5 Hz,
1H), 1.71e1.81 (m 2H), 1.57e1.62 (m, 2H), 1.25e1.44 (m, 6H), 0.90 (t,
5.1.4.3. 4,40-Tetramethylene-disinomenine (3c). Yield 61%; white
solid; mp 124e125 ꢀC. 1H NMR (300 MHz, CDCl3)
6.70 (s, 4H), 5.47
d
(s, 2H), 4.11e4.23 (m, 6H), 3.77 (s, 6H), 3.48 (s, 6H), 3.15 (s, 2H), 2.98
(d, J ¼ 16.8 Hz, 4H), 2.76 (td, J ¼ 17.7, 4.8 Hz, 2H), 2.46e2.52 (m, 4H),
J ¼ 7.2 Hz); 13C NMR (75 MHz, CDCl3)
d 192.0, 171.6, 152.3, 149.9,
139.5, 129.4, 128.6, 125.3, 114.2, 110.9, 55.9, 55.7, 54.7, 49.5, 46.3,
44.7, 41.7, 40.0, 36.2, 34.3, 31.3, 28.6, 24.6, 24.2, 22.4, 13.9. Positive
ESIeMS m/z: 442 (M þ H)þ, HRMS: calcd for C26H36NO5 (M þ H),
442.2593; found, 442.2563.
2.41 (s, 6H), 1.91e2.04 (m, 12H); 13C NMR (75 MHz, CDCl3)
d 193.9,
152.6, 151.6, 148.3, 130.2, 130.1, 122.6, 115.6, 111.6, 72.1, 56.7, 55.9,
54.9, 50.0, 47.2, 46.1, 42.8, 41.0, 37.4, 27.0, 24.8. Positive ESIeMS m/z:
713 (M þ H)þ. HRMS: calcd for C42H53N2O8 (M þ H), 713.3802;
found, 713.3782.
5.1.3.5. 4-Capryloyl-sinomenine (2e). Yield 91%; white solid; mp
70e72 ꢀC. 1H NMR (300 MHz, CDCl3)
d
6.88 (d, J ¼ 8.4 Hz, 1H), 6.72
5.1.4.4. 4,40-Pentamethylene-disinomenine (3d). Yield 65%; white
(d, J ¼ 8.4 Hz, 1H), 5.46 (d, J ¼ 1.8 Hz, 1H), 3.85 (d, J ¼ 15.9 Hz, 1H),
3.70 (s, 3H), 3.47 (s, 3H), 3.17 (t, J ¼ 4.2 Hz, 1H), 2.96e3.06 (br, 2H),
2.47e2.76 (m, 4H), 2.46 (d, J ¼ 15.9 Hz, 1H), 2.41 (s, 3H), 2.09 (td,
J ¼ 12.0, 2.4 Hz, 1H), 1.71e1.89 (m, 3H), 1.58 (d, J ¼ 12.0 Hz, 1H),
1.29e1.41 (m, 8H), 0.88 (t, J ¼ 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3)
solid; mp 100e102 ꢀC. 1H NMR (300 MHz, CDCl3)
d 6.70 (d,
J ¼ 8.4 Hz, 2H), 6.67 (d, J ¼ 8.4 Hz, 2H), 5.47 (s, 2H), 4.18 (d, J ¼ 15.9
Hz, 2H), 4.05 (dt, J ¼ 19.8, 6.9 Hz, 4H), 3.76 (s, 6H), 3.47 (s, 6H), 3.13
(t, J ¼ 3.9 Hz, 2H), 2.97 (d, J ¼ 17.1 Hz, 4H), 2.71 (dd, J ¼ 18.0, 4.8 Hz,
2H), 2.44e2.51 (m, 4H), 2.39 (s, 6H), 1.86e2.03 (m, 10H), 1.66 (d,
d
192.2, 171.5, 152.2, 149.5, 139.4, 129.8, 129.7, 125.1, 115.0, 110.6,
J ¼ 15.0, 7.5 Hz, 2H); 13C NMR (75 MHz, CDCl3)
d 194.0, 152.6, 151.6,
56.1, 55.6, 54.6, 49.9, 46.4, 45.7, 42.5, 40.4, 36.9, 34.2, 31.5, 28.8, 28.7,
24.6, 24.0, 22.4, 13.9. Positive ESIeMS m/z: 456 (M þ H)þ, HRMS:
calcd for C27H38NO5 (M þ H), 456.2750; found, 456.2714.
148.2, 130.1, 130.0, 122.6, 115.5,111.4, 72.3, 56.7, 55.9, 54.9, 49.9, 47.1,
46.1, 42.8, 40.8, 37.4, 30.4, 24.7, 22.4. Positive ESIeMS m/z: 727
(M þ H)þ. HRMS: calcd for C43H55N2O8 (M þ H), 727.3958; found,
727.3941.
5.1.3.6. 4-Nonanoyl-sinomenine (2f). Yield 82%; white solid; mp
66e68 ꢀC. 1H NMR (300 MHz, CDCl3)
d
6.90 (d, J ¼ 8.4 Hz, 1H), 6.75
5.1.4.5. 4,40-Hexamethylene-disinomenine (3e). Yield 63%; white
(d, J ¼ 8.4 Hz, 1H), 5.45 (d, J ¼ 1.5 Hz, 1H), 3.85 (d, J ¼ 15.9 Hz, 1H),
3.71 (s, 3H), 3.47 (s, 3H), 3.28 (t, J ¼ 3.6 Hz, 1H), 3.03 (br, 2H), 2.79
(dd, J ¼ 18.6, 5.4 Hz,1H), 2.50e2.71 (m, 3H), 2.49 (d, J ¼ 15.9 Hz,1H),
2.45 (s, 3H), 2.15 (td, J ¼ 12.3, 2.4 Hz, 1H), 2.02 (d, J ¼ 4.8 Hz, 1H),
1.90 (td, J ¼ 12.6, 4.5 Hz, 1H), 1.73e1.76 (m, 2H), 1.59 (d, J ¼ 12.6 Hz,
1H), 1.23e1.40 (m, 9H), 0.88 (t, J ¼ 6.9 Hz, 3H); 13C NMR (75 MHz,
solid; mp 68e69 ꢀC. 1H NMR (300 MHz, CDCl3)
d
6.72 (d, J ¼ 8.4 Hz,
2H), 6.68 (d, J ¼ 8.4 Hz, 2H), 5.49 (s, 2H), 4.25 (d, J ¼ 16.5 Hz, 2H),
4.03e4.11 (m, 4H), 3.77 (s, 6H), 3.48 (s, 6H), 3.16 (s, 2H), 2.99 (d,
J ¼ 18.0 Hz, 4H), 2.73 (dd, J ¼ 18.0, 4.8 Hz, 2H), 2.50 (t, J ¼ 4.8 Hz,
2H), 2.41 (s, 6H), 2.35 (d, J ¼ 6.3 Hz, 2H), 1.90e1.99 (m, 8H),
1.57e1.70 (m, 6H); 13C NMR (75 MHz, CDCl3)
d 193.9, 152.5, 151.5,
CDCl3)
d
192.0, 171.7, 152.3, 150.0, 139.5, 129.6, 129.1, 125.2, 114.4,
148.1, 130.1, 130.0, 122.5, 115.5, 111.4, 72.2, 56.5, 55.8, 54.8, 49.9, 47.1,
46.1, 42.7, 40.8, 37.3, 30.3, 25.9, 24.6. Positive ESIeMS m/z: 741
(M þ H)þ. HRMS: calcd for C44H57N2O8 (M þ H), 741.4115; found,
741.4106.
110.8, 56.1, 55.8, 54.7, 49.7, 46.4, 45.0, 42.0, 40.2, 36.5, 34.3, 31.7,
29.1, 29.0, 28.9, 24.7, 24.1, 22.5, 14.0. Positive ESIeMS m/z: 470
(M þ H)þ, HRMS: calcd for C28H40NO5 (M þ H), 470.2906; found,
470.2872.
5.1.4.6. 4,40-Heptamethylene-disinomenine (3f). Yield 66%; white
5.1.4. General procedure for synthesis of ether homodimers (3aei)
To a solution of sinomenine (1) (329 mg, 1 mmol) and dibro-
moalkane (0.5 mmol) in dry acetone (2 mL) was added potassium
carbonate (690 mg, 5 mmol). The mixture was stirred at 60 ꢀC until
the starting material was no longer detected by TLC. The reaction
mixture was then filtered and solvent was removed under vacuum
to afford the crude product, which was purified by gel column
chromatography to give title compounds as a foamy pale-white
solid.
solid; mp 57e59 ꢀC. 1H NMR (300 MHz, CDCl3)
d
6.70 (t, J ¼ 9.0 Hz,
4H), 5.48 (d, J ¼ 1.5 Hz, 2H), 4.18 (d, J ¼ 15.9 Hz, 2H), 4.00e4.07 (m,
4H), 3.77 (s, 6H), 3.49 (s, 6H), 3.20 (br t, 2H), 2.96e3.02 (br, 4H), 2.77
(dd, J ¼ 18.0, 5.4 Hz, 2H), 2.56 (d, J ¼ 11.1 Hz, 2H), 2.48 (d, J ¼ 15.9 Hz,
2H), 2.45 (s, 6H), 1.86e2.07 (m, 10H), 1.50 (br, 6H); 13C NMR
(75 MHz, CDCl3) d 193.6, 152.4, 151.5, 148.1, 130.0, 122.3, 115.0, 111.3,
72.2, 56.6, 55.6, 54.7, 49.6, 47.1, 45.7, 42.5, 40.6, 37.0, 30.2, 29.4, 25.8,
24.5. Positive ESIeMS m/z: 755 (M þ H)þ, HRMS: calcd for
C45H59N2O8 (M þ H), 755.4271; found, 755.4262.
5.1.4.1. 4,40-Dimethylene-disinomenine (3a). Yield 36%; white solid;
5.1.4.7. 4,40-Octamethylene-disinomenine (3g). Yield 70%; white
mp 210e212 ꢀC. 1H NMR (300 MHz, CDCl3)
d
6.19e6.25 (m, 4H),
solid; mp 58e60 ꢀC. 1H NMR (300 MHz, CDCl3)
d
6.68 (d, J ¼ 8.1 Hz,
5.41 (d, J ¼ 1.5 Hz, 2H), 4.37 (d, J ¼ 15.6 Hz, 2H), 3.64 (s, 6H), 3.62 (d,
J ¼ 1.5 Hz, 2H), 3.46 (s, 6H), 3.18 (t, J ¼ 4.2 Hz, 2H), 3.00 (br, 2H),
2.75e2.81 (m, 2H), 2.54 (dd, J ¼ 6.0, 2.7 Hz, 2H), 2.31e2.46 (m, 4H),
2H), 6.65 (d, J ¼ 8.1 Hz, 2H), 5.46 (d, J ¼ 1.5 Hz, 2H), 4.16 (d,
J ¼ 16.2 Hz, 2H), 3.98e4.07 (m, 4H), 3.74 (s, 6H), 3.46 (s, 6H), 3.12 (t,
J ¼ 4.2 Hz, 2H), 2.96 (d, J ¼ 17.1 Hz, 4H), 2.70 (dd, J ¼ 18.0, 5.4 Hz,
2H), 2.46e2.50 (m, 4H), 2.39 (s, 6H), 1.97 (t, J ¼ 4.5 Hz, 2H),
1.84e1.87 (m, 8H), 1.42e1.48 (m, 8H); 13C NMR (75 MHz, CDCl3)
2.28 (s, 6H), 1.86e2.03 (m, 8H); 13C NMR (75 MHz, CDCl3)
d 193.8,
152.3, 144.9, 143.0, 128.1, 127.7, 122.8, 114.9, 110.1, 56.4, 56.0, 54.6,
49.0, 47.1, 45.4, 42.5, 40.5, 35.7, 35.6, 21.5. Positive ESIeMS m/z: 685
(M þ H)þ, HRMS: calcd for C40H49N2O8 (M þ H), 685.3489; found,
685.3472.
d
194.0, 152.6, 151.6, 148.3, 130.2, 130.1, 122.5, 115.5, 111.5, 72.4, 56.6,
55.9, 54.9, 50.0, 47.2, 46.2, 42.8, 40.9, 37.4, 30.5, 29.7, 26.0, 24.7.
Positive ESIeMS m/z: 769 (M þ H)þ. HRMS: calcd for C46H61N2O8
(M þ H), 769.4428; found, 769.4419.
5.1.4.2. 4,40-Trimethylene-disinomenine (3b). Yield 53%; white
solid; mp 101e103 ꢀC. 1H NMR (300 MHz, CDCl3)
d
6.99e6.66 (m,
5.1.4.8. 4,40-Nonamethylene-disinomenine (3h). Yield 68%; white
4H), 5.46 (s, 2H), 4.35e4.14 (m, 6H), 3.78 (s, 6H), 3.47 (s, 6H),
3.16e3.14 (m, 2H), 2.95e2.76 (m, 4H), 2.72 (dd, J ¼ 12.0, 6.0 Hz, 2H),
2.53e2.45 (m, 6H), 2.41 (s, 6H), 2.07e1.87 (m, 8H); 13C NMR
solid; mp 75e78 ꢀC. 1H NMR (300 MHz, CDCl3)
d
6.70 (t, J ¼ 8.7 Hz,
4H), 5.47 (d, J ¼ 1.8 Hz, 2H), 4.18 (d, J ¼ 15.9 Hz, 2H), 4.03e4.09 (m,
4H), 3.77 (s, 6H), 3.50 (s, 6H), 3.18 (t, J ¼ 4.5 Hz, 2H), 2.93e3.02 (m,
4H), 2.75 (dd, J ¼ 18.3, 4.8 Hz, 2H), 2.46e2.56 (m, 4H), 2.44 (s, 6H),
1.86e2.05 (m, 12H), 1.39e1.46 (m, 10H); 13C NMR (75 MHz, CDCl3)
(75 MHz, CDCl3) d 193.6, 152.3, 151.3, 148.0, 129.8, 122.7, 122.4, 115.1,
111.4, 69.5, 56.4, 55.7, 54.6, 49.8, 47.0, 45.9, 42.5, 40.7, 37.2, 31.3,
24.4. Positive ESIeMS m/z: 699 (M þ H)þ, HRMS: calcd for
C41H51N2O8 (M þ H), 699.3645; found, 699.3625.
d
193.7, 152.4, 151.4, 148.0, 130.0, 129.9, 122.3, 115.3, 111.2, 72.2, 56.4,
55.6, 54.6, 49.7, 47.0, 46.0, 42.6, 40.7, 37.2, 30.2, 29.5, 29.4, 25.8, 24.5.