4
0
J.-H. Liu et al.
3.2.15 Betulinic acid-6-nitrooxy-hexyl
ester (9d)
NMR (300 MHz, CDCl ): d 0.82 (s, 3H,
3
CH ), 0.84 (s, 3H, CH ), 0.92 (s, 3H, CH ),
3
3
3
0
.93 (s, 3H, CH ), 0.97 (s, 3H, CH ), 1.69
3 3
Compound 9d was prepared from 8d and
AgNO as described for 3a to afford a
white solid in 78% yield. m.p. 69–718C.
(
s, 3H, 30-CH ), 2.63 (t, 2H, J ¼ 6.3 Hz,
3
3
COCH ), 2.66 (t, 2H, J ¼ 6.3 Hz,
2
2
1
IR nmax (KBr, cm ): 3454, 2962, 1723,
COCH ), 3.45 (brs, 1H, 3a-H), 4.24
2
1
694, 1628; H NMR (300 MHz, CDCl ):
(t, 2H, J ¼ 6.0 Hz, OCH ), 4.50 (t, 2H,
1
d 0.92 (s, 3H, CH ), 0.95 (s, 3H, CH ),
2
3
J ¼ 4.2 Hz, OCH ), 4.60 (s, 1H, 29-H),
2
3
3
4.73 (s, 1H, 29-H), 7.60–7.65 (m, 2H,
ArH), 7.73–7.79 (m, 2H, ArH), 8.06 (d,
0
.98 (s, 3H, CH ), 1.02 (s, 3H, CH ), 1.07
3 3
(s, 3H, CH ), 1.68 (s, 3H, 30-CH ), 2.99
3 3
2
H, J ¼ 7.8 Hz, ArH); ESI-MS: m/z 823
(
m, 1H, 19-H), 4.13 (m, 2H, COOCH2),
.46 (t, 2H, J ¼ 6.6 Hz, OCH ), 4.61
2
M 2 H] .
[
4
2
(
s, 1H, 29-H), 4.73 (s, 1H, 29-H); ESI-
þ
MS: m/z 617 [M þ NH ] .
4
3.3.3 3-O-{4-[2-(2-Oxy-3-
phenylsulfonyl-1,2,5-oxadiazol-4-oxy)
propoxy]}-succinyl-betulinic acid (12b)
3
.3 Synthesis of compounds 12a–d
3
.3.1 3-O-Succinyl-betulinic acid (11)
Compound 12b was prepared from 10b
and 11 as described for 12a to afford a
white solid in 45% yield. m.p. 180–1828C.
A solution of BA (2.74 g, 6 mmol) and
succinic anhydride (2.4 g, 24 mmol) in
anhydrous pyridine (20 ml) was kept under
reflux for 10 h. Then, the reaction mixture
was poured into boiled water (100 ml),
cooled and stirred for 10 min, and then
acidized with 10% HCl to a pH of 5. The
mixture was extracted with EtOAc (3 £
2
1
IR nmax (KBr, cm ): 3449, 2929, 1726,
1
627, 1375, 1166; H NMR (300 MHz,
1
CDCl ): d 0.80 (s, 3H, CH ), 0.81 (s, 3H,
3
3
CH ), 0.83 (s, 3H, CH ), 0.94 (s, 3H, CH ),
3
3
3
0
2
.96 (s, 3H, CH ), 1.69 (s, 3H, 30-CH ),
3 3
.62 (t, 2H, J ¼ 5.4 Hz, COCH ), 3.47
2
(
brs, 1H, 3a-H), 4.30 (t, 2H, J ¼ 6.3 Hz,
2 2
3
0 ml). The combined organic layer was
OCH ), 4.49 (t, 2H, J ¼ 6.0 Hz, OCH ),
washed with water and saturated NaCl
solution sequentially, dried over anhy-
drous Na SO , and concentrated in vacuo.
4
7
2
.61 (s, 1H, 29-H), 4.73 (s, 1H, 29-H),
.60–7.65 (m, 2H, ArH), 7.73–7.79 (m,
2
4
H, ArH), 8.06 (d, 2H, J ¼ 7.5 Hz, ArH);
The crude product was recrystallized in
MeOH for three times as a white solid
2
ESI-MS: m/z 837 [M 2 H] .
(2.90 g, 87%).
3
.3.4 3-O-{4-[2-(2-Oxy-3-
3
.3.2 3-O-{4-[2-(2-Oxy-3-phenylsulfonyl-
,2,5-oxadiazol-4-oxy)ethoxy]}-succinyl-
phenylsulfonyl-1,2,5-oxadiazol-4-oxy)-1-
methyl-ethoxy]}-succinyl-betulinic acid
(12c)
1
betulinic acid (12a)
A solution of 10a (61.7 mg, 0.22 mmol),
1
Compound 12c was prepared from 10c and
11 as described for 12a to afford a white
solid in 42% yield. m.p. 160–1628C. IR
nmax (KBr, cm ): 3452, 2944, 1732,
1
1625, 1384, 1170; H NMR (300 MHz,
1 (100 mg, 0.18 mmol), DMAP (22 mg,
.18 mmol), and EDCI (35 mg, 0.18 mmol)
0
in anhydrous CH Cl (10 ml) was stirred at
2
1
2
2
reflux for 24 h. After filtration, the filtrate
was evaporated to dryness in vacuo, and
the product was purified by column
CDCl ): d 0.77 (s, 3H, CH ), 0.80 (s, 3H,
3
3
CH ), 0.82 (s, 3H, CH ), 0.93 (s, 3H, CH ),
3
3
3
chromatography (CHCl –MeOH; 100:1)
3
0.97 (s, 3H, CH ), 1.33 (d, 3H, J ¼ 6.2 Hz,
3
to give compound 12a (59 mg, 40%). m.
OCHCH ), 1.69 (s, 3H, 30-CH ), 2.60 (s,
3
3
2
p. 165–1678C. IR nmax (KBr, cm ):
1
4H, 2 £ COCH ), 3.00 (m, 1H, 19-H), 3.56
2
1
453, 2930, 1728, 1627, 1372, 1170; H
3
(brs, 1H, 3a-H), 4.45–4.48 (m, 3H, OCH ,
2