J.J. Ramírez-Espinosa et al. / European Journal of Medicinal Chemistry 87 (2014) 316e327
325
washed with hexane and absolute ethanol). Mixture reaction was
stirred at 0 ꢁC for 30 min. Alkyl halide (2.1 equiv.) was added
dropwise over a period of 5 min, then mixture reaction was placed
under microwave radiation in equipment CEM at 50 ꢁC. Solvent was
concentrated under vacuum and de crude reaction was purified by
FCC.
4.1.6.3. (3
0.66 mmol), Na (37 mg, 1.65 mmol), THF/DMF (6 mL), 1-
iodopropane (240 mg, 140 L, 1.41 mmol) 3.5 h reaction. FCC: (n-
b)-3-propoxyolean-12-en-28-oic acid (11). OA (300 mg,
m
hexane/AcOEt 90:10 v/v) affording 118 mg product, 36% yield. TLC:
Rf 0.57 (n-hexane-AcOEt 80:20); white powder; m.p. 150e153.
D
[a
]
þ 77 (c 0.2, CHCl3). IR (CHCl3) nmax 3394, 2945, 2858, 1717,
20
1460, 1381, 1251, 1158, 1028, 997, 937, 748, 667 cmꢀ1
;
1H NMR
4.1.6.1. (3
0.44 mmol), Na (25 mg, 1.09 mmol), THF/DMF (6 mL), iodomethane
(130 mg, 60 L, 0.92 mmol), 1 h reaction. FCC: (n-hexane/AcOEt
90:10 v/v) affording 125 mg product, 61% yield. TLC: Rf 0.48 (n-
b
)-3-methoxyolean-12-en-28-oic acid (9). OA (200 mg,
(CDCl3, 400 MHz)
d
5.28 (1H, dd, J ¼ 3.2, 3.2 Hz, H-12), 4.00 (1H, cd,
J ¼ 6.8, 2.4 Hz, H-Aa), 3.95 (1H, cd, J ¼ 6.8, 2.4 Hz, H-Ab), 3.21 (1H,
dd, J ¼ 10.8, 4.8 Hz, H-3), 2.75 (1H, dd, J ¼ 14.0,4.8 Hz, H-18), 1.98
(1H, m, H-16a), 1.85 (1H, m, H-16b), 1.62 (2H, m, H-11), 1.71 (1H, m,
H-7a), 1.65 (1H, m, H-19a), 1.61 (1H, m, H-1a), 1.59 (2H, m, H-15b),
1.54 (1H, m, H-7a), 1.51 (2H, m, H-9), 1.52 (2H, m, H-6), 1.34 (1H, m,
H-21a), 1.18 (1H, m, H-21b), 1.16 (1H, m, H-19b), 1.13 (3H, s, H-27),
0.99 (3H, s, H-23), 0.96 (2H, t, J ¼ 7.6 Hz, HeB), 0.94 (3H, t, J ¼ 7.6 Hz,
HeC), 0.95 (1H, m, H-1b), 0.92 (3H, s, H-30), 0.91 (3H, s, H-25), 0.90
(3H, s, H-29), 0.77 (3H, s, H-24), 0.74 (3H, s, H-26), 0.72 (1H, m, H-5);
m
D
hexane-AcOEt 80:20); white powder; m.p. 194e197; OR [
(c 0.2, CHCl3); IR (CHCl3) nmax 3337, 2941, 2925, 2864, 1715, 1458,
1384, 1188, 1161, 1127, 1030, 993, 907, 740, 657 cmꢀ1 1H NMR
(CDCl3, 400 MHz) 5.28 (1H, m, H-12), 3.62 (3H, s, H-A), 3.21 (1H,
a]
20 þ 96
;
d
dd, J ¼ 10.8, 5.2 Hz, H-3), 2.86 (1H, dd, J ¼ 14.0, 4.4 Hz, H-18), 2.00
(1H, m, H-16a), 1.88 (2H, m, H-11), 1.72 (1H, m, H-22a), 1.70 (2H, m,
H-15), 1.65 (1H, m, H-19a), 1.63 (1H, m, H-16b), 1.60 (1H, m, H-1a),
1.59 (2H, m, H-2), 1.55 (1H, m, H-6a), 1.54 (1H, m, H-9), 1.53 (1H, m,
H-22b),1.49 (1H, m, H-7a), 1.40 (1H, m, H-6b), 1.32 (1H, m, H-21a),
1.29 (1H, m, H-7b), 1.28 (1H, m, H-22), 1.19 (1H, m, H-21b), 1.14 (1H,
m, H-19b), 1.12 (3H, s, H-27), 0.98 (3H, s, H-23),0.96 (1H, m, H-1b),
0.93 (3H, s, H-30), 0.91 (3H, s, H-25), 0.89 (3H, s, H-29), 0.78 (3H, s,
H-24), 0.74 (1H, m, H-5), 0.71 (3H, s, H-26); 13C NMR (CDCl3,
100 MHz) 178.50 (s, C-28), 144.00 (s, C-13), 122.58 (d, C-12), 79.24
(d, C-3), 55.46 (d, C-5), 51.73 (c, C-A), 47.86 (d, C-9), 46.95 (s, C-17),
46.11 (t, C-19), 41.87 (s, C-14), 41.53 (d, C-18), 39.51 (s, C-8), 38.98 (t,
C-1), 38.98(s, C-4), 38.67 (s, C-10), 34.30 (t, C-21), 33.30 (c, C-29),
33.30 (t, C-22), 33.30 (t, C-7), 30.91 (s, C-20), 28.86 (t, C-15), 28.32
(c, C-23), 27.96 (t, C-2), 26.16 (c, C-27), 23.80 (c, C-30), 23.63 (t, C-
11), 23.30 (t, C-16), 18.56 (t, C-6), 17.06 (c, C-26), 15.79 (c, C-24),
15.52 (c, C-25); EIMS m/z: 470 [Mþ] (9), 262 (70), 203 (100), 202
(28), 187 (24), 133 (15), 119 (15), 84 (42), 69 (12), 57 (11). HR CIMS
[M þ H]þ 471.3815 [M þ H]þ (Calculated for C31H51O3, 471.3760).
13C NMR (CDCl3,100 MHz)
d 176.53 (s, C-28),144.81 (s, C-13), 122.22
(d, C-12), 79.19 (d, C-3), 65.78 (t, C-A), 55.87 (d, C-5), 47.78 (d, C-9),
46.92 (s, C-17), 46.04 (t, C-19), 41.54 (d, C-18), 39.44 (s, C-14), 41.86
(s, C-8), 38.93 (s, C-4), 38.61 (t, C-1), 37.18 (s, C-10), 34.03 (t, C-21),
33.31 (c, C-29), 32.88 (t, C-7), 32.52 (t, C-22), 30.90 (s, C-20), 28.29
(c, C-23), 27.80 (t, C-2), 27.37 (t, C-15), 26.08 (c, C-27), 23.85 (c, C-
30), 23.58 (t, CeB), 23.23 (t, C-11), 18.50 (t, C-6), 17.06 (c, C-26),
15.79 (c, C-24), 15.50 (c, C-25), 10.79 (c, CeC); EIMS m/z: 498 [Mþ]
(18), 411 (22), 410 (21), 290 (65), 203 (100), 189 (25), 119 (9), 105 (8).
HR EIMS m/z 498.4042 [Mþ] (Calculated for C33H54O3, 498.4073).
4.1.7. (3b)-olean-12-ene-3,28-diol (8)
To a cooled (0 ꢁC) solution of LiAlH4 (100 mg, 2.63 mmol) in dry
THF (10 mL) was added dropwise OA (300 mg, 0.66 mmol) in dry
THF (5 mL) under N2 atmosphere. Suspension was stirred at 0 ꢁC for
1 h, allowed to rise to room temperature and kept for 30 min.
Mixture reaction was refluxed 8 h and then stirred at room tem-
perature overnight. Reaction was quenched by addition of a
mixture of 2 mL of H2O distilled and 5 mL of NaOH 10%, stirring 1 h.
Precipitate was filtered and washed with ethyl acetate (3 ꢂ 5 mL).
Organic phase was separated and aqueous layer was further
extracted with ethyl acetate (3 ꢂ 5 mL). Combined organic phases
were dried over anhydrous Na2SO4 and evaporated under reduced
pressure. FCC: (n-hexane/acetone 90:10 v/v) affording 175 mg
4.1.6.2. (3
0.55 mmol), Na (30 mg, 1.37 mmol), THF/DMF (6 mL), bromoethane
(125 mg, 90 L, 1.15 mmol), 2 h reaction. FCC: (n-hexane/AcOEt
90:10 v/v) affording 160 mg product, 60% yield. TLC: Rf 0.62 (n-
b)-3-ethoxyolean-12-en-28-oic acid (10). OA (250 mg,
m
D
hexane-AcOEt 80:20); white powder; m.p. 157.3e159.7 [
(c 0.2, CHCl3). IR (CHCl3) nmax 3300e2600 (COOH), 2938, 2973,1722,
1682, 1459, 1381, 1361, 1183, 1110, 1075, 825, 732 cmꢀ1 1H NMR
(CDCl3, 400 MHz)
5.27 (1H, dd, J ¼ 3.2, 3.2 Hz, H-12), 3.66 (1H, cd,
a]
20 þ 67
;
product, 60% yield. TLC: Rf 0.41 (n-hexane-acetone 80:20); yellow
D
d
powder; m.p. 201e204 [Lit. 229 ꢁC]; [
a]
þ 76 (c 0.2, CHCl3)
20
J ¼ 6.8, 2.4 Hz, H-A), 3.35 (1H, cd, J ¼ 6.8, 2.4 Hz, H-A), 2.82 (1H, dd,
J ¼ 13.6, 4.8 Hz, H-18), 2.75 (1H, m, H-3), 1.97 (1H, ddd, J ¼ 13.6,13.6,
4.0 Hz, H-15a), 1.88 (2H, m, H-11), 1.78 (1H, m, H-16a), 1.76 (1H, m,
H-7a), 1.72 (1H, m, H-2a), 1.70 (1H, m, H-15b), 1.64 (1H, m, H-19a),
1.63 (1H, m, H-1a), 1.54 (1H, m, H-7a), 1.54 (1H, m, H-9), 1.53 (1H, m,
H-16b), 1.51 (1H, m, H-6a), 1.43 (H, m, H-22a), 1.33 (1H, m, H-21a),
1.39 (1H, m, H-6b), 1.28 (H, m, H-22b), 1.21 (1H, m, H-21b), 1.17 (3H,
t, J ¼ 6.8 Hz, HeB), 1.15 (1H, m, H-19b),1.11 (3H, s, H-27),1.08 (1H, m,
H-2b), 0.95 (3H, s, H-23), 0.91 (1H, m, H-1b), 0.91 (3H, s, H-30), 0.90
(3H, s, H-25), 0.89 (3H, s, H-29), 0.77 (3H, s, H-24), 0.74 (3H, s, H-26),
[Lit. þ41 (c 0.6, MeOH)] [16]; IR (CHCl3) nmax 3329, 2920, 2856,1710,
1464, 1389, 1359, 1094, 1044, 1006 cmꢀ1; 1H NMR (CDCl3, 400 MHz)
d
5.19 (1H, dd, J ¼ 3.6, 3.6 Hz, H-12), 3.57 (1H, d, J ¼ 11.2 Hz, H-28a),
3.23 (1H, dd, J ¼ 11.2, 4.4Hz, H-3), 3.22 (1H, d, J ¼ 11.2 Hz, H-28b),
1.99 (1H, m, H-18),1.98 (1H, m, H-16a),1.87 (1H, m, H-16b),1.76 (1H,
m, H-19a), 1.74 (2H, m, H-2), 1.63 (1H, m, H-1a), 1.61 (2H, m, H-15),
1.56 (2H, m, H-6), 1.55 (1H, m, H-9), 1.53 (1H, m, H-22), 1.53 (1H, m,
H-7a), 1.33 (2H, m, H-21), 1.32 (1H, m, H-22), 1.30 (1H, m, H-7b), 1.18
(2H, m, H-11), 1.16 (3H, s, H-27), 1.08 (1H, m, H-19b), 0.99 (3H, s, H-
23), 0.97 (1H, m, H-1b), 0.94 (3H, s, H-26), 0.93 (3H, s, H-24), 0.89
(3H, s, H-29), 0.87 (3H, s, H-30), 0.79 (3H, s, H-25), 0.74 (1H, m, H-5);
0.74 (1H, m, H-5); 13C NMR (CDCl3, 100 MHz)
d 184.42 (s, C-28),
143.82 (s, C-13), 122.92 (d, C-12), 86.96 (d, C-3), 65.41 (t, C-A), 56.05
(d, C-5), 47.89 (d, C-9), 46.77 (s, C-17), 46.13 (t, C-19), 41.78 (d, C-18),
41.13 (s, C-14), 39.55 (s, C-8), 38.91(s, C-4), 38.69 (t, C-1), 37.29 (s, C-
10), 34.03 (t, C-21), 33.29 (c, C-29), 32.85 (t, C-22), 32.67 (t, C-7),
30.88 (s, C-20), 28.39 (c, C-23), 27.91 (t, C-2), 26.17 (c, C-27), 23.81
(c, C-30), 23.67 (t, C-11), 23.40 (t, C-16), 23.13 (t, C-15), 18.49 (t, C-6),
17.41 (c, C-26), 16.65 (c, C-24), 15.87 (c, CeB), 15.54 (c, C-25); EIMS
m/z: 484 [Mþ] (10), 424 (19), 411 (13), 276 (33), 248 [retro Diel-
seAlder] (64), 203 (100), 189 (22), 175 (11), 133 (11), 119 (10), 95
(11), 69 (12), 57 (9). HR CIMS [M þ H]þ 485.3904 [M þ H]þ
(Calculated for C32H53O3, 485.3916).
13C NMR (CDCl3, 100 MHz)
d (multiplicity and assignment) 144.37
(s, C-13), 122.50 (d, C-12), 79.19 (d, C-3), 69.85 (t, C-28), 55.31 (d, C-
5), 47.73 (d, C-9), 46.62 (t, C-19), 46.04 (s, C-17), 42.50 (d, C-18), 41.
87 (s, C-8), 39.93 (s, C-14), 38.94 (s, C-4), 38.75 (t, C-1), 37.09 (s, C-
10), 34.25 (t, C-21), 33.40 (c, C-29), 32.72 (t, C-22), 31.22 (t, C-7),
31.14 (s, C-20), 28.27 (c, C-23), 27.33 (t, C-15), 26.14 (c, C-27), 25.70
(t, C-2), 23.77 (c, C-30), 23.70 (t, C-16), 22.12 (t, C-11), 18.53 (t, C-6),
16.89 (c, C-26), 15.79 (c, C-24), 15.71 (c, C-25); EIMS m/z: 442 [Mþ]
(5), 279 (9), 256 (32), 213 (13), 203 (64),167 (16),149 (51),129 (115),
91 (27), 69 (37), 50 (100). HR EIMS m/z 442.3830 [Mþ] (Calculated
for C30H50O2, 442.3811).