2606 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 7
Zhang et al.
mixture was filtered, neutralized with triethylamine, and
evaporated to dryness. The residue was dissolved in dichlo-
romethane and washed with water, ice-cold 1 M hydrochloric
acid, and saturated sodium bicarbonate solution. The colorless
solid (R:â ) 2:1) of compound 17 (310 mg, 72% yield) was
obtained after purification on a column of silica gel using ethyl
acetate-hexane (1:3) as eluant: 1H NMR (250 MHz, CDCl3)
5.24 (d, J ) 3.4 Hz, H-1R), 5.20 (m, H-3R), 4.88 (m, H-3â), 4.80
(dd, J ) 1.9 Hz, J ) 9.4 Hz, H-1â), 4.63 (t, J ) 9.6 Hz, H-4),
4.00 (m, H-5R), 3.43 (m, H-5â), 2.26 (m, H-2âeq), 2.13 (m,
H-2Req), 1.70 (m, H-2âax), 1.60 (m, H-2Rax), 1.11 (d, J ) 6.2
Hz, H-6â), 1.05 (d, J ) 6.2 Hz, H-6R).
2,5-Dihydro-3-[1-(tert-butyloxycarbonyl)-1H-indol-3-
yl]-4-[1-(2-deoxy-3,4-di-O-acetyl-L-rhamnopyranosyl)-1H-
indol-3-yl]-1H-pyrrole-2,5-dione (18). To a solution of 13
(1.50 g, 3.40 mmol) in THF (100 mL) were added 17 (1.95 g,
8.41 mmol) and triphenylphosphine (2.20 g, 8.41 mmol). The
mixture was cooled to -78 °C, and then DEAD (1.33 mL, 8.41
mmol) was added dropwise. The mixture was allowed to reach
room temperature and stirred at room temperature for 15 h,
and then water was added. After extraction with ethyl acetate,
the combined organic phase was dried over Na2SO4. The
solvent was removed, and the residue was purified through
column chromatography on silica gel using benzene-ethyl
acetate (9:1) to give unreacted substrate 13 (1.0 g) and the
anomeric mixture 18 (0.7 g, 32%, R:â ) 1:2.5) as an orange
solid: 1H NMR (250 MHz, CDCl3) 5.24 (dd, J ) 1.75 Hz, J )
11 Hz, H-1′â), 5.96 (d, J ) 4.7 Hz, H-1′R).
2,5-Dihydro-3-(1H-indol-3-yl)-4-[1-(2-deoxy-3,4-di-O-
acetyl-â-L-rhamnopyranosyl)-1H-indol-3-yl]-1H-pyrrole-
2,5-dione(19) and 2,5-Dihydro-3-(1H-indol-3-yl)-4-[1-(2-
deoxy-3,4-di-O-acetyl-R-L-rhamnopyranosyl)-1H-indol-3-
yl]-1H-pyrrole-2,5-dione (20). A solution of 18 (310 mg, 0.47
mmol) in 88% formic acid (40 mL) was stirred at room
temperature and monitored by TLC hourly. After 6 h, the
reaction was completed. Trimethylamine was added dropwise
until neutralization. Saturated aqueous NaOAc was added.
After extraction with ethyl acetate, the combined organic phase
was dried over Na2SO4. The solvent was removed, and the
residue was purified by prep-TLC (benzene-ethyl acetate, 8:1)
to afford 19 (red solid, 170 mg) and 20 (red solid, 68 mg) with
91% yield.
19: HRMS (M + Na)+ (ESI+) calcd for C31H29N3O7Na+
578.1898, found 578.1896. 1H NMR (400 MHz, CDCl3) 8.52
(1H, s, NH), 7.72 (1H, s), 7.67 (1H, s), 7.34 (1H, d, J ) 8.2
Hz), 7.30 (1H, d, J ) 8.2 Hz), 7.11 (1H, t, J ) 7.4 Hz), 7.06
(1H, t, J ) 7.4 Hz), 6.97 (2H, d, J ) 8.8 Hz), 6.77 (2H, dd, J )
7.3 Hz, J ) 12.6 Hz), 5.65 (1H, d, J ) 10.3 Hz, H-1′), 5.14
(1H, m, H-3′), 4.87 (1H, t, J ) 9.6 Hz, H-4′), 3.75 (1H, m, H-5′),
3.17 (3H, s, NCH3), 2.47 (1H, m, H-2eq), 2.23 (1H, m, H-2ax),
2.08 (3H, s, COCH3), 2.04 (3H, s, COCH3), 1.24 (3H, d, J )
6.3 Hz, H-6′). 13C NMR (400 MHz, CDCl3) 18.2 (C6′), 21.2, 21.3
(CH3CO), 24.6 (NCH3), 36.1 (C2′), 71.4, 73.3, 74.1, 81.4 (C1′,
C3′, C4′, C5′), 110.5, 111.6, 120.9, 121.4, 122.5, 122.9, 123.1,
123.2, 128.4, 128.8 (C tert arom), 107.6, 107.9, 125.7, 126.9,
127.5, 128.7, 136.1, 136.3 (C quat arom), 170.4, 170.7, 172.6,
172.7 (CdO). 20: HRMS (M + Na)+ (ESI+) calcd for C31H29N3O7-
Na+ 578.1897, found 578.1895. 1H NMR (400 MHz, CDCl3) 8.59
(1H, s, NH), 7.88 (1H, s), 7.80 (1H, d, J ) 2.7 Hz), 7.58 (1H, d,
J ) 8.3 Hz), 7.29 (1H, d, J ) 8.2 Hz), 7.20 (1H, d, J ) 8.0 Hz),
7.11 (1H, t, J ) 8.2 Hz), 7.03 (1H, t, J ) 8.1 Hz), 6.88 (2H, t,
J ) 8.1 Hz), 6.72 (1H, t, J ) 8.0 Hz), 5.99 (1H, d, J ) 4.4 Hz,
H-1′), 4.87 (2H, m, H-4′, H-3′), 3.31 (1H, m, H-5′), 3.18 (3H, s,
NCH3), 2.75 (1H, m, H-2eq), 2.17 (1H, m, H-2ax), 2.03 (3H, s,
COCH3), 2.02 (3H, s, COCH3), 1.12 (3H, d, J ) 6.3 Hz, H-6′).
13C NMR (400 MHz, CDCl3) 17.6 (C6′), 21.2, 21.3 (CH3CO), 24.6
(NCH3), 32.7 (C2′), 67.9, 69.9, 73.6, 80.5 (C1′, C3′, C4′, C5′), 111.5,
112.4, 120.6, 121.6, 122.4, 122.6, 123.1, 123.4, 129.1, 129.6 (C
tert arom), 107.5, 108.0, 125.4, 127.4, 127.6, 128.9 136.5, 137.0
(C quat arom), 170.4, 170.8, 172.6, 172.7 (CdO).
Air was continuously bubbled through the reaction while was
irradiated with a medium-pressure mercury lamp equipped
with a Vycor filter for 8 h. Benzene was added to the reaction
every 2 h to keep the solvent volume constant. The solvent
was removed, and the residue was dissolved in EtOAc and
washed with aqueous Na2S2O3 and brine. The organic phase
was dried over Na2SO4. After removal of the solvent, the
residue was purified by Prep-TLC using EtOAc-hexane (1:9)
as developing solvent to give the product 21 (41 mg, 82% yield)
as a yellow solid: HRMS (M + Na)+ (ESI+) calcd for C31H27N3O7-
Na+ 576.1741, found 576.1751. 1H NMR (400 MHz, CDCl3)
10.15 (1H, s, NH), 9.25 (1H, d, J ) 7.8 Hz), 9.15 (1H, d, J )
7.9 Hz), 7.59-7.40 (6H, m), 6.16 (1H, dd, J ) 2.9 Hz, J ) 10.7
Hz, H-1′), 5.29 (2H, m, H-3′, H-4′), 4.15 (1H, m, H-5′), 3.21
(3H, s, NCH3), 2.25 (2H, m, H-2), 2.17 (3H, s, COCH3), 1.90
(3H, s, COCH3), 1.67 (3H, d, J ) 6.2 Hz, H-6′). 13C NMR (400
MHz, CDCl3) 19.1 (C6′), 21.1, 21.2 (CH3CO), 24.1 (NCH3), 36.1
(C2′), 70.7, 73.9, 75.2, 82.7 (C1′, C3′, C4′, C5′), 109.7, 111.5, 121.7,
122.5, 126.1, 126.5, 127.8, 127.9, (C tert arom), 118.9, 119.7,
120.1, 121.8, 122.7, 123.3, 128.5, 130.0, 140.6, 140.7 (C quat
arom), 170.2, 170.3, 170.3, 170.4 (CdO).
6-Methyl-12-(2-deoxy-3,4-di-O-acetyl-R-L-rhamnopy-
ranosyl)-6,7,12,13-tetrahydroindolo[2,3-a]pyrrolo[3,4-c]car-
bazole-5,7-dione (22). Following the same procedure de-
scribed for 21, compound 22 was obtained from 20 as a yellow
solid (57% yield): HRMS (M + Na)+ (ESI+) calcd for C31H27N3O7-
Na+ 576.1741, found 576.1756. 1H NMR (500 MHz, CDCl3)
10.46 (1H, s, NH), 9.36 (1H, d, J ) 7.6 Hz), 9.26 (1H, d, J )
8.2 Hz), 7.61-7.39 (6H, m), 6.16 (1H, d, J ) 9.2 Hz, H-1′), 5.25
(1H, br, H-4′), 5.02 (1H, br, H-3′), 4.87 (1H, m, H-5′), 3.32 (3H,
s, NCH3), 2.60, 1.83 (2H, 2m, H-2), 2.32 (3H, s, COCH3), 2.24
(3H, s, COCH3), 1.86 (3H, d, J ) 7.3 Hz, H-6′). 13C NMR (500
MHz, CDCl3) 16.0 (C6′), 21.5, 21.8 (CH3CO), 24.1 (NCH3), 32.1
(C2′), 68.9, 68.9, 74.8, 75.8, (C1′, C3′, C4′, C5′), 109.7, 110.9, 121.2,
122.2, 126.3, 126.6, 127.5, 127.6, (C tert arom), 118.5, 120.0,
120.1, 121.3, 122.7, 123.2, 128.4, 129.7, 140.4, 140.5 (C quat
arom), 169.1, 169.6, 170.2 (CdO).
6-Methyl-12-(2-deoxy-â-L-rhamnopyranosyl)-6,7,12,13-
tetrahydroindolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-di-
one (5). A solution of tetrabutylammonium fluoride (4 mL,
1.0 M in THF) was added to a solution of 21 (70 mg, 0.07 mmol)
in THF (10 mL). The mixture was refluxed for 15 h, diluted
with EtOAc (80 mL), washed with water, and dried over Na2-
SO4. The solvent was removed, and the residue was purified
on a column of silica gel using MeOH-CH2Cl2 (1:50) as eluent
to give the product 5 (63 mg, 90% yield) as a yellow solid:
HRMS (M + Na)+ (ESI+) calcd for C27H23N3O5Na+ 492.1530,
found 492.1529. 1H NMR (500 MHz, DMSO) 11.35 (1H, s, NH),
9.09 (1H, d, J ) 7.9 Hz), 8.97 (1H, d, J ) 8.0 Hz), 8.02 (1H, d,
J ) 8.4 Hz), 7.73 (1H, d, J ) 8.2 Hz), 7.55 (2H, m), 7.33 (2H,
m), 6.61 (1H, dd, J ) 2.4 Hz, J ) 11.1 Hz, H-1′), 5.41 (1H, br,
H-4′), 5.09 (1H, br, HO-3′), 3.94 (1H, m, H-5′), 3.34 (2H, m,
H-3′, HO-4′), 3.03(3H, s, NCH3), 3.11, 2.25 (2H, m, H-2), 1.49
(3H, d, J ) 6.1 Hz, H-6′). 13C NMR (500 MHz, DMSO) 19.3
(C6′), 24.4 (NCH3), 39.1 (C2′), 71.1, 76.1, 77.5, 83.0 (C1′, C3′, C4′,
C5′), 112.6, 113.7, 121.4, 121.9, 125.2, 125.5, 127.8, 128.1, (C
tert arom), 118.1, 118.2, 119.5, 120.7, 121.4, 122.9, 128.8,
129.1, 140.5, 141.3 (C quat arom), 170.1, 170.2 (CdO).
6-Methyl-12-(2-deoxy-R-L-rhamnopyranosyl)-6,7,12,13-
tetrahydroindolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-di-
one (6). Followed the same procedure described for 5, 6 was
obtained from 22 as a yellow solid (70% yield): HRMS (M +
Na)+ (ESI+) calcd for C27H23N3O5Na+ 492.1530, found 492.1523.
1H NMR (400 MHz, DMSO) 12.06 (1H, s, NH), 9.20 (1H, d,
J ) 8.1 Hz), 9.09 (1H, d, J ) 8.0 Hz), 7.79 (1H, d, J ) 8.4 Hz),
7.60 (3H, m), 7.38 (2H, m), 6.69 (2H, m, H-1′, 4′), 5.56 (1H, d,
J ) 3.0 Hz, HO-3′), 4.53 (1H, m, H-3′), 4.19 (1H, br, H-5′), 3.80
(1H, br, HO-4′), 3.(3H, s, NCH3), 2.73, 1.83 (2H,m, H-2), 1.47
(3H, d, J ) 6.1 Hz, H-6′). 13C NMR (500 MHz, DMSO) 16.0
(C6′), 24.5 (NCH3), 34.5 (C2′), 68.6, 69.2, 73.9, 77.9 (C1′, C3′, C4′,
C5′), 110.4, 112.2, 121.1, 121.7, 125.3, 125.6, 127.8, 128.1, (C
tert arom), 117.4, 118.1, 119.1, 120.9, 121.5, 121.8, 128.5,
129.4, 140.3, 141.2 (C quat arom), 170.43, 170.45 (CdO).
6-Methyl-12-(2-deoxy-3,4-di-O-acetyl-â-L-rhamnopy-
ranosyl)-6,7,12,13-tetrahydroindolo[2,3-a]pyrrolo[3,4-c]car-
bazole-5,7-dione (21). A red solution of 19 (50 mg, 0.09
mmol) in benzene (150 mL) was treated with iodine (1 mg).