206
J. Wiemann et al. / European Journal of Medicinal Chemistry 106 (2015) 194e210
2362w, 1734m, 1646w, 1534w, 1457w, 1347w, 1245m, 1134w, 1106w,
1030w, 980w, 882w, 776w, 668w, 610w cmꢁ1 1H NMR (400 MHz,
CDCl3):
¼ 4.68 (s, 1H, CHa (29)), 4.62 (br, 1H, NH), 4.58 (s, 1H, CHb
[M þ Na]þ), 1207.3 (48%, [2M þ H]þ), 1229.3 (100%, [2M þ Na]þ);
analysis calcd for C39H57NO4 (603.87): C 77.57, H 9.51, N 2.32;
found: C 77.36, H 9.69, N 2.18.
;
d
(29)), 4.46 (dd, J ¼ 9.4, 6.5 Hz, 1H, CH (3)), 4.26 (d, J ¼ 10.8 Hz, 1H,
CHa (28)), 3.82 (d, J ¼ 10.3 Hz, 1H, CHb (28)), 3.16 (br, 2H, CH2 (34)),
2.44 (dt, J ¼ 11.2, 5.9 Hz, 1H, CH (19)), 2.03 (s, 3H, CH3 (32)),
2.02e1.92 (m, 1H, CHa (21)), 1.85e1.76 (m, 1H, CHa (16)), 1.76e1.70
(m, 2H, CHa (22) þ CHa (15)), 1.68 (s, 3H, CH3 (30)), 1.66e1.62 (m, 2H,
CHa (1) þ CH (13)), 1.61e1.53 (m, 5H, CH (18) þ CH2 (12) þ CH2 (2)),
1.53e1.44 (m, 3H, CH2 (35) þ CHa (6)), 1.44e1.35 (m, 6H, CH2
(7) þ CHb (21) þ CH2 (11) þ CHb (6)), 1.33e1.24 (m, 7H, CH (9) þ CH2
(36) þ CH2 (37) þ CH2 (38)), 1.24e1.15 (m, 1H, CHb (16)), 1.08e0.99
(m, 2H, CHb (22) þ CHb (15)), 1.04 (s, 3H, CH3 (25)), 0.98e0.93 (m,
1H, CHb (1)), 0.96 (s, 3H, CH3 (27)), 0.88 (t, J ¼ 6.4 Hz, 3H, CH3 (39)),
0.84 (s, 3H, CH3 (23)), 0.84 (s, 3H, CH3 (26)), 0.83 (s, 3H, CH3 (24)),
0.79e0.76 (m, 1H, CH (5)) ppm; 13C NMR (100 MHz, CDCl3):
4.3.34. (3b) 3-Hydroxylup-20(29)-en-28-N-ethylcarbamate (36)
Deacetylation of 31 (0.98 g, 1.77 mmol) with potassium hy-
droxide (0.25 g, 5.3 mmol) in THF (30 mL) and MeOH (10 mL) for 2
days at 25 ꢀC as described above, followed by chromatography
(silica gel, hexanes/ethyl acetate, 7:3) gave 36 (0.86 g, 94.5%) as a
colorless solid; RF ¼ 0.13 (silica gel, hexanes/ethyl acetate, 8:2);
m.p.: 223e225 ꢀC; [
a]
¼ þ10.1ꢀ (c ¼ 0.29, CHCl3); IR (KBr):
D
n
¼ 3432br, 2938s, 1689m, 1640w, 1536w, 1458w, 1375w, 1248m,
1024w, 883m, 543w cmꢁ1
;
1H NMR (400 MHz, CDCl3):
d
¼ 4.67 (s,
1H, CHa (29)), 4.62 (br, 1H, NH), 4.57 (s, 1H, CHb (29)), 4.24 (d,
J ¼ 10.8 Hz, 1H, CHa (28)), 3.83 (d, J ¼ 10.5 Hz, 1H, CHb (28)), 3.21 (br,
2H, CH2 (32)), 3.17 (dd, J ¼ 11.2, 5.0 Hz, 1H, CH (3)), 2.44 (dt, J ¼ 11.1,
5.8 Hz, 1H, CH (19)), 1.98 (ddd, J ¼ 19.5, 11.4, 7.0 Hz, 1H, CHa (21)),
1.86e1.72 (m, 3H, CHa (15) þ CHa (16) þ CHa (22)), 1.72e1.54 (m, 5H,
CH (18) þ CH (13) þ CHa (1) þ CHa (2) þ CHa (12)), 1.67 (s, 3H, CH3
(30)), 1.54e1.48 (m, 2H, CHb (2) þ CHa (6)), 1.44e1.33 (m, 5H, CH2
(7) þ CHb (6) þ CHa (11) þ CHb (21)), 1.29e1.17 (m, 3H, CH (9) þ CHb
(11) þ CHb (16)), 1.13 (t, J ¼ 7.2 Hz, 3H, CH3 (33)), 1.10e0.99 (m, 3H,
CHb (12) þ CHb (15) þ CHb (22)), 1.03 (s, 3H, CH3 (25)), 0.96 (s, 3H,
CH3 (27)), 0.96 (s, 3H, CH3 (23)), 0.89 (dt, J ¼ 12.8, 4.4 Hz, 1H, CHb
(1)), 0.81 (s, 3H, CH3 (26)), 0.75 (s, 3H, CH3 (24)), 0.67e0.65 (m, 1H,
d
¼ 171.0 (C]O, C31), 157.2 (C]O, C33), 150.3 (C]CH2, C20), 109.8
(H2C]C, C29), 80.9 (CH, C3), 62.9 (CH2, C28), 55.4 (CH, C5), 50.3
(CH, C9), 48.8 (CH, C18), 47.7 (CH, C19), 46.6 (Cq, C17), 42.7 (Cq, C14),
41.0 (CH2, C34), 40.9 (Cq, C8), 38.4 (CH2, C1), 37.8 (Cq, C4), 37.5 (CH,
C13), 37.1 (Cq, C10), 34.6 (CH2, C22), 34.1 (CH2, C7), 31.5 (CH2, C37),
30.0 (CH2, C35), 29.8 (CH2, C16), 29.7 (CH2, C21), 27.9 (CH3, C23),
27.1 (CH2, C15), 26.4 (CH2, C36), 25.2 (CH2, C12), 23.7 (CH2, C2), 22.5
(CH2, C38), 21.3 (CH3, C32), 20.8 (CH2, C11), 19.1 (CH3, C30), 18.2
(CH2, C6), 16.5 (CH3, C24), 16.1 (CH3, C26), 16.0 (CH3, C25), 14.7 (CH3,
C27), 14.0 (CH3, C39) ppm; MS (ESI, MeOH): m/z ¼ 612.2 (60%,
[M þ H]þ), 634.5 (19%, [M þ Na]þ),1223.6 (100%, [2M þ H]þ),1245.6
(26%, [2M þ Na]þ); analysis calcd for C39H65NO4 (611.94): C 76.55, H
10.71, N 2.29; found: C 76.37, H 10.84, N 2.19.
CH (5)) ppm; 13C NMR (100 MHz, CDCl3):
d
¼ 157.0 (C]O, C31),
150.3 (C]CH2, C20), 109.7 (H2C]C, C29), 79.0 (CH, C3), 62.9 (CH2,
C28), 55.3 (CH, C5), 50.4 (CH, C9), 48.8 (CH, C18), 47.7 (CH, C19), 46.6
(Cq, C17), 42.7 (Cq, C14), 40.9 (Cq, C8), 38.8 (Cq, C4), 38.7 (CH2, C1),
37.5 (CH, C13), 37.1 (Cq, C10), 35.9 (CH2, C32), 34.6 (CH2, C22), 34.2
(CH2, C7), 29.8 (CH2, C16), 29.7 (CH2, C21), 28.0 (CH3, C23), 27.4
(CH2, C2), 27.1 (CH2, C15), 25.2 (CH2, C12), 20.8 (CH2, C11), 19.1 (CH3,
C30), 18.3 (CH2, C6), 16.1 (CH3, C26), 16.0 (CH3, C25), 15.3 (CH3, C24),
15.3 (CH3, C33), 14.7 (CH3, C27) ppm; MS (ESI, MeOH): m/z ¼ 514.1
(14%, [M þ H]þ), 536.4 (6%, [M þ Na]þ), 1027.5 (100%, [2M þ H]þ),
1049.4 (96%, [2M þ Na]þ); analysis calcd for C33H55NO3 (513.79): C
77.14, H 10.79, N 2.73; found: C 77.04, H 10.90, N 2.59.
4.3.33. (3b) 3-Acetyloxylup-20(29)-en-28-N-phenylcarbamate (35)
Microwave assisted reaction (7 h, 120 ꢀC) of 30 (1 g, 2.1 mmol) in
dry THF (5 mL) with phenyl isocyanate (0.74 g, 0.67 mL, 6.2 mmol)
as described above, followed by chromatography (silica gel, hex-
anes/ethyl acetate, 9:1) gave 35 (1.08 g, 87.1%) as a colorless solid;
RF ¼ 0.84 (silica gel, hexanes/ethyl acetate, 7:3); m.p.: 221e223 ꢀC;
[
a
]
¼ þ13.2ꢀ (c ¼ 0.44, CHCl3); IR (KBr):
¼ 3431m, 3080w, 2948s,
n
D
2873m, 1737s, 1647w, 1602m, 1523s, 1501w, 1442s, 1391w, 1374m,
1311m, 1246m, 1204s, 1178w, 1105w, 1084w, 1054m, 1030m, 978m,
898w, 872w, 848w, 757m, 693w, 545w, 510w cmꢁ1; UVevis (CHCl3):
4.3.35. (3b) 3-Hydroxylup-20(29)-en-28-N-propylcarbamate (37)
Deacetylation of 32 (0.53 g, 0.93 mmol) with potassium hy-
droxide (0.10 g, 1.8 mmol) in THF (5 mL)/MeOH (5 mL) for 1 day as
decribed above, followed by chromatography (silica gel, hexanes/
ethyl acetate, 8:2) gave 37 (0.46 g, 93.0%) as a colorless solid;
RF ¼ 0.26 (silica gel, hexanes/ethyl acetate, 8:2); m.p.: 111e114 ꢀC;
lmax (log e) ¼ 236.1 (4.17) nm; 1H NMR (400 MHz, CDCl3):
d
¼ 7.39
(d, J ¼ 7.9 Hz, 2H, HC]C (35/350)), 7.31 (t, J ¼ 7.9 Hz, 2H, HC]C (36/
360)), 7.06 (t, J ¼ 7.3 Hz,1H, HC]C (37)), 6.61 (br,1H, NH), 4.70 (s,1H,
CHa (29)), 4.60 (s,1H, CHb (29)), 4.47 (dd, J ¼ 10.2, 5.9 Hz,1H, CH (3)),
4.37 (d, J ¼ 10.8 Hz, 1H, CHa (28)), 3.95 (d, J ¼ 10.8 Hz, 1H, CHb (28)),
2.47 (dt, J ¼ 11.0, 5.8 Hz, 1H, CH (19)), 2.04 (s, 3H, CH3 (32)),
2.03e1.96 (m, 1H, CHa (21)), 1.92e1.82 (m, 1H, CHa (16)), 1.81e1.71
(m, 2H, CHa (22) þ CHa (15)), 1.69 (s, 3H, CH3 (30)), 1.68e1.66 (m, 1H,
CH (13)),1.66e1.59 (m, 3H, CHa (1) þ CH2 (12)),1.60e1.55 (m, 3H, CH
(18) þ CH2 (2)), 1.53e1.48 (m, 1H, CHa (6)), 1.46e1.36 (m, 6H, CH2
(7) þ CHb (21) þ CH2 (11) þ CHb (6)), 1.33e1.19 (m, 2H, CH (9) þ CHb
(16)), 1.15e1.02 (m, 2H, CHb (22) þ CHb (15)), 1.05 (s, 3H, CH3 (25)),
1.02e0.93 (m, 1H, CHb (1)), 0.98 (s, 3H, CH3 (27)), 0.85 (s, 3H, CH3
(23)), 0.84 (s, 3H, CH3 (26)), 0.84 (s, 3H, CH3 (24)), 0.79e0.76 (m, 1H,
[
a
]
¼ þ10.5ꢀ (c ¼ 0.31, CHCl3); IR (KBr):
¼ 3456br, 2941s, 2869s,
n
D
2362w, 1702s, 1528m, 1460m, 1375w, 1244m, 1106w, 1045m, 883w,
668w cmꢁ1
;
1H NMR (400 MHz, CDCl3):
d
¼ 4.68 (s, 1H, CHa (29)),
4.64 (br, 1H, NH), 4.58 (s, 1H, CHb (29)), 4.25 (d, J ¼ 10.7 Hz, 1H, CHa
(28)), 3.84 (d, J ¼ 10.6 Hz, 1H, CHb (28)), 3.18 (dd, J ¼ 11.2, 5.0 Hz, 1H,
CH (3)), 3.14 (br, 2H, CH2 (32)), 2.44 (dt, J ¼ 11.1, 5.7 Hz, 1H, CH (19)),
2.03e1.92 (m, 1H, CHa (21)), 1.87e1.79 (m, 1H, CHa (16)), 1.79e1.69
(m, 2H, CHa (22) þ CHa (15)), 1.67 (s, 3H, CH3 (30)), 1.66e1.61 (m, 3H,
CHa (1) þ CH (13) þ CHa (12)), 1.61e1.55 (m, 3H, CH (18) þ CH2 (2)),
1.55e1.47 (m, 3H, CH2 (33) þ CHa (6)), 1.44e1.33 (m, 5H, CH2
(7) þ CHb (21) þ CHa (11) þ CHb (6)),1.29e1.17 (m, 3H, CH (19) þ CHb
(16) þ CHb (11)), 1.10e0.99 (m, 3H, CHb (22) þ CHb (15) þ CHb (12)),
1.04 (s, 3H, CH3 (25)), 0.97 (s, 3H, CH3 (23)), 0.96 (s, 3H, CH3 (27)),
0.92 (t, J ¼ 7.3 Hz, 3H, CH3 (34)), 0.89e0.84 (m, 1H, CHb (1)), 0.82 (s,
3H, CH3 (26)), 0.75 (s, 3H, CH3 (24)), 0.69e0.66 (m, 1H, CH (5)) ppm;
CH (5)) ppm; 13C NMR (100 MHz, CDCl3):
d
¼ 171.0 (C]O, C31),
154.0 (C]O, C33), 150.1 (C]CH2, C20), 137.9 (Cq, C34), 129.0 (CH,
C36/360), 123.4 (CH, C37), 118.6 (CH, C35/350), 109.9 (H2C]C, C29),
80.9 (CH, C3), 63.6 (CH2, C28), 55.4 (CH, C5), 50.3 (CH, C9), 48.8 (CH,
C18), 47.7 (CH, C19), 46.6 (Cq, C17), 42.7 (Cq, C14), 40.9 (Cq, C8), 38.4
(CH2, C1), 37.8 (Cq, C4), 37.6 (CH, C13), 37.1 (Cq, C10), 34.5 (CH2, C22),
34.1 (CH2, C7), 29.8 (CH2, C16), 29.6 (CH2, C21), 27.9 (CH3, C23), 27.1
(CH2, C15), 25.2 (CH2, C12), 23.7 (CH2, C2), 21.3 (CH3, C32), 20.8
(CH2, C11), 19.1 (CH3, C30), 18.2 (CH2, C6), 16.5 (CH3, C24), 16.1 (CH3,
C26), 16.1 (CH3, C25), 14.7 (CH3, C27) ppm; MS (ESI, MeOH): m/
z ¼ 604.1 (6%, [M þ H]þ), 621.0 (10%, [M þ NH4]þ), 626.3 (24%,
13C NMR (100 MHz, CDCl3):
d
¼ 157.2 (C]O, C31), 150.3 (C]CH2,
C20), 109.7 (H2C]C, C29), 79.0 (CH, C3), 63.0 (CH2, C28), 55.3 (CH,
C5), 50.4 (CH, C9), 48.8 (CH, C18), 47.7 (CH, C19), 46.6 (Cq, C17), 42.8
(CH2, C32), 42.7 (Cq, C14), 40.9 (Cq, C8), 38.8 (Cq, C4), 38.7 (CH2, C1),
37.5 (CH, C13), 37.1 (Cq, C10), 34.6 (CH2, C22), 34.2 (CH2, C7), 29.9
(CH2, C16), 29.7 (CH2, C21), 28.0 (CH3, C23), 27.4 (CH2, C2), 27.1 (CH2,