G.S.R. Subba Rao et al. / Tetrahedron 64 (2008) 11541–11548
11545
1
1
726, 1682, 1644, 1455, and 1386; H NMR (300 MHz, CDCl
3
):
d
5.75
(134 mg, 1.92 mmol), sodium acetate (312 mg, 1.92 mmol) in acetic
acid (1 mL) and water (1 mL). The mixture was homogenized by the
addition of methanol (2 mL) and refluxed for a period of 5 h. The
solvents were removed under reduced pressure and the residue
was diluted with water (15 mL) and extracted with ethyl acetate
(
1H, s), 2.97 (1H, m), 2.64 (1H, m), 2.41 (1H, s), 2.41–0.87 (40H, m);
1
3
C NMR (75 MHz, CDCl
1.0, 55.4, 48.2, 47.8, 45.3, 43.8, 43.3, 40.9, 39.7, 37.7, 36.7, 34.2, 32.1,
1.9, 30.9, 28.6, 28.4, 26.5, 26.3, 23.3, 21.4, 18.8, 18.5, and 15.6.
3
): d 217.3, 199.7, 181.2, 169.8, 128.4, 76.6,
6
3
(
3ꢁ15 mL). The combined organic layer was washed with brine,
4.1.3. Methyl 3
b-hydroxy-11-oxo-30-norolean-12-en-30-oate 9
dried over sodium sulfate, and filtered. The solvent was removed
under vacuum and the resulting solid was recrystallized from
dichloromethane/methanol to give a colorless solid 13 (0.64 g,
A solution of ethereal diazomethane (in excess) was added to
a suspension of glycyrrhetinic acid 7 (9.4 g, 20 mmol) in methanol
ꢀ
ꢀ
(
150 mL) at 0 C. The reaction mixture was allowed to stand over-
80%). Mp 279–280 C (from dichloromethane/methanol); (Found:
night. The excess of diazomethane was quenched with acetic acid
six drops) and the mixture was concentrated under vacuum. The
C, 75.7; H, 9.05; N, 2.4. C32
H
45NO
4
requires: C, 75.7; H, 8.9; N, 2.7%.)
ꢂ1
1
(
n
max (neat)/cm 2972, 1730, 1658, 1620, 1460, 1385, and 870;
H
solid was recrystallized from methanol/dichloromethane mixture
to give colorless crystals 9 (9.6 g, 99%). Mp 254–256 C (from
3
NMR (300 MHz, CDCl ): d 7.97 (1H, s), 5.72 (1H, s), 3.71 (3H, s), 3.65
ꢀ
13
(1H, d, J 15.1 Hz), 2.50 (1H, s), and 2.16–0.84 (38H, m); C NMR
(75 MHz, CDCl ): 198.4, 176.2,171.7,169.0, 149.8,128.5, 108.8, 59.9,
dichloromethane/methanol); (Found: C, 76.65; H, 10.1. C31
H
48
O
4
3
d
ꢂ1
requires: C, 76.85; H, 9.9%.)
and 1467; 1H NMR (300 MHz, CDCl
.20 (1H, m), 2.80 (1H, d, J 13.5 Hz), 2.30 (1H, s), and 2.15–0.65 (41H,
n
max (neat)/cm 3357, 2946,1722, 1656,
53.2, 51.5, 48.1, 45.1, 43.8, 43.2, 41.2, 38.3, 37.7, 35.9, 34.6, 31.8 (2C),
3
):
d
5.63 (1H, s), 3.69 (3H, s),
31.0, 28.8, 28.5, 28.2, 26.5, 26.4, 23.2, 21.5, 18.2, 18.0, and 15.6; m/z
þ
3
(DI) 507 (M ), 135 and 83 (100%).
13
m); C NMR (75 MHz, CDCl
4.9, 51.5, 48.2, 45.2, 43.9, 43.0, 41.1, 39.1 (2C), 37.7, 37.0, 32.8, 31.7,
1.0, 28.5, 28.2, 28.1, 27.3, 26.4, 23.4, 18.6, 17.4, 16.3, and 15.6; m/z
3
): d 199.2, 176.2, 168.2, 128.5, 78.5, 61.7,
5
4.1.7. Methyl 2-cyano-3,11-dioxo-30-norolean-1,12-dien-30-oate 5
The isoxazole 13 (270 mg, 0.5 mmol) in diethyl ether (5 mL) was
added to a stirred solution of sodium (60 mg, 2.6 mmol) in dry
3
(
þ
DI) 484 (M ), 317, 276, 175, and 135 (100%).
ꢀ
methanol (3 mL) under an atmosphere of argon at 0 C. It was
4
.1.4. Methyl 3,11-dioxo-30-norolean-12-en-30-oate 11
Following the procedure for the synthesis of 10 from 8 described
allowed to stir for 1 h. Cold water (5 mL) was added to the reaction
mixture and the organic layer was washed thoroughly with 5%
potassium hydroxide solution (3ꢁ10 mL). The combined alkaline
extracts were acidified and extracted with ethyl acetate (3ꢁ15 mL).
The organic layer was washed with brine, dried over sodium sul-
fate, and concentrated under reduced pressure. The crude residue
earlier, the oxidation of the methyl ester 9 (9.21 g, 19 mmol) gave 11
as amorphous solid (8.80 g, 95%) [This compound was found to be
identical to that obtained by diazomethane esterification of the acid
ꢀ
10.] Mp 248–250 C (from dichloromethane/methanol); (Found: C,
ꢂ1
7
2
CDCl
(
1
4
2
7.6; H, 9.8. C31
942, 1725, 1704, 1655, 1625, 1463, and 1386; H NMR (300 MHz,
): 5.68 (1H, s), 3.69 (3H, s), 2.97 (1H, m), 2.62 (1H, m), 2.40
1H, s), and 2.37–0.83 (39H, m); C NMR (75 MHz, CDCl
98.4, 176.1, 168.7, 128.3, 60.9, 55.3, 51.5, 48.2, 47.5, 45.1, 43.8, 43.2,
1.1, 39.6, 37.7, 36.6, 33.9, 32.1, 31.7, 31.0, 28.5, 28.2, 26.5, 26.4, 26.3,
H
46
O
4
requires: C, 77.2; H, 9.5%.)
n
max (neat)/cm
14 (248 mg, 91%) was directly used in the next step without puri-
1
ꢂ1
fication.
n
max (KBr)/cm 2963, 2204, 1726, 1657, 1461, 1388, and
1
3
d
801; H NMR (300 MHz, CDCl
3
):
d
5.70, (1H, s), 3.70 (3H, s), 2.40
13
þ
3
):
d
215.6,
(1H, s), and 2.34–0.83 (40H, m); m/z (DI) 507 (M ), 310, 276, and
135 (100). A mixture of the crude cyano-ketone 14 (63 mg,
0.12 mmol) and DDQ (33 mg, 0.14 mmol) in benzene (3 mL) was
refluxed for 8 h. After cooling the reaction mixture to ambient
temperature, acetone was added till it became homogenous and
the clear solution was filtered through a pad of alumina. The filtrate
was concentrated and the solid residue was recrystallized from
dichloromethane/methanol to give the pure cyano-enone 5 (40 mg,
þ
3.3, 21.3, 18.7, 18.5, and 15.5; m/z (DI) 482 (M ), 317, 276, and 135
(
100%).
4
3
.1.5. Methyl 2-hydroxymethylene-3,11-dioxo-30-norolean-12-en-
0-oate 12
To an ice-cold suspension of sodium methoxide (440 mg, 8 mmol)
ꢀ
65%). Mp 237–239 C (from dichloromethane/methanol); (Found:
in dry benzene (20 mL) was added a solution of ketone 11 (1.9 g,
mmol) and ethyl formate (634 mg, 8 m mol) overa period of 10 min
C, 76.1; H, 8.5; N, 2.8. C32
H
43NO
4
requires: C, 76.0; H, 8.6; N, 2.8%.)
ꢂ1
4
n
max (neat)/cm 2951, 2232, 1727, 1685, 1655, 1610, 1457, 1387, 802,
1
under an atmosphere of nitrogen. The resulting mixture was allowed
to stand overnight at room temperature. Ice water (20 mL) was
added and the two layers separated. The organic layer was extracted
with 20% sodium hydroxide solution (3ꢁ20 mL). The combined
aqueous layer was acidified with 2 N hydrochloric acid and extracted
with ethyl acetate (3ꢁ20 mL). The ethyl acetate layer was washed
with water, brine, dried over sodium sulfate, and concentrated under
vacuum. Recrystallization of the solid from dichloromethane/meth-
and 736; H NMR (300 MHz, CDCl
(3H, s), 2.70 (1H, s), and 2.20–0.84 (37H, m); C NMR (75 MHz,
CDCl ): 197.4, 196.8, 176.2, 171.9, 170.9, 127.8, 114.5, 113.3, 54.2,
3
): d 8.49 (1H, s), 5.78 (1H, s), 3.71
13
3
d
51.7, 51.6, 48.3, 45.5, 44.9, 43.8, 43.4, 41.1, 39.5, 37.6, 31.7, 31.6, 31.0,
28.5, 28.1, 27.4, 26.4, 26.2, 23.3, 21.4, 19.4, 18.8 and 18.0; m/z (DI) 83
(100%).
Crystal data: Compound 5: C32
tal, crystal system: monoclinic, space group: P2(1), cell parameters:
43 4
H O N, MW¼505, colorless crys-
ꢀ
anol afforded the pure colorless formyl derivative 12 (1.60 g, 78%). Mp
a¼7.282 (4) Å, b¼12.262 (8) Å, c¼16.173 (10) Å,
b
¼94.57 (1),
ꢀ
3
ꢂ3
ꢂ1
2
9
1
32–234 C (from dichloromethane/methanol); (Found: C, 75.1; H,
V¼1440.00 (6) Å , Z¼2, D
c
¼1.162 g cm , F(000)¼544.0,
m
¼0.08 mm
.
ꢂ1
.15. C32
H
46
O
4
requires: C, 75.3; H, 9.0%.)
nmax (KBr)/cm 3438, 2934,
Total number of l.s. parameters¼342, R
1
¼0.0494 for 4676 F
o
>4
s
(F
o
)
1
732, 1653, 1618, 1457, and 1386; H NMR (300 MHz, CDCl
3
):
d
14.84
and 0.0655 for all 5812 data. wR
2
¼0.1230, GOF¼1.019, restrained
(
(
(
5
3
1H, d, J 3.0 Hz), 8.62 (1H, d, J 3.0 Hz), 5.71 (1H, s), 3.71 (3H, s), 3.46
GOF¼1.024 for all data. Crystallographic data (without structure
factor) have deposited with the Cambridge Crystallographic Data
Center and the depository number is CCDC 213948.
13
1H, d, J 14.1 Hz), 2.40 (1H, s), and 2.15–0.84 (38H, m); C NMR
75 MHz, CDCl ): 198.5, 189.2, 188.2, 176.1, 169.1, 128.4, 105.5, 59.5,
2.2, 51.5, 48.1, 44.8, 43.8, 43.1, 41.2, 39.9, 39.6, 37.7, 36.1, 31.7, 31.6,
1.0, 28.5, 28.4, 28.1, 26.4, 26.3, 23.2, 20.8,18.7,18.2, and 14.6; m/z (DI)
3
d
4.1.8. Synthesis of 5 via allylic bromination–dehydrobromination
A mixture of the isoxazole 13 (270 mg, 0.5 mmol), NBS (98 mg,
þ
10 (M ), 317, 276, 135, and 83 (100%).
5
0.55 mmol), AIBN (catalytic amount) in chloroform (5 mL) was
4
.1.6. Isoxazole derivative of the methyl ester of glycyrrhetinic
allowed to reflux under the influence of tungsten lamp for 6 h. The
solution was cooled, and the precipitated succinimide was filtered.
Removal of the solvent afforded the crude bromo compound 15,
which was added to an ice-cold solution of sodium (46 mg,
acid 13
The formyl derivative 12 (0.80 g, 1.6 mmol) in benzene (6 mL)
was mixed with a solution of hydroxylamine hydrochloride