of 21sreacts with TBAF14 to leading to deprotection of the
TBDMS group and simultaneous cyclization to the desired CC-
1065 analogue 5.
A versatile photochemical procedure was used as a key step
in the preparation of a new and potentially enhanced CC-1065
analogue. This preparation of phenanthrenes is equally useful
for the preparation of heterocyclic analogues thereof.
mixture was stirred at room temperature under argon during 8 min.
The solvent was removed and the resulting crude material was
purified by column chromatography in silica (10 × 1.5 cm L),
delivering compound 7 (161 mg) in 92% overall yield from
benzindol 18. Mp: 185-189 °C (EtOAc/methanol). Rf: 0.08
1
(EtOAc). H NMR (CDCl3, 250 MHz) δ: 7.61 (s, 1H); 6.24 (s,
1H); 5.73 (s, 1H); 3.93 (s, 3H); 3.88 (s, 3H); 3.87 (s, 3H); 3.79
(dd, J ) 10.8 and 5.1 Hz, 1H); 3.63 (d, J ) 10.5 Hz, 1H); 3.25 (m,
1H); 1.92 (dd, J ) 7.6 and 3.2 Hz); 1.10 (t, J ) 3.8 Hz, 1H). 13C
NMR (CDCl3, 62.83 MHz) δ: 183.3 (C); 172.4 (C); 152.2 (C);
149.2 (C); 144.5 (C); 130.6 (C); 125.5 (C); 105.4 (CH); 95.7 (CH);
61.8 (OCH3); 61.1 (OCH3); 56.4 (OCH3); 50.7 (CH2); 31.7 (C);
26.8 (CH); 26.0 (CH2). MS (EI, 75 eV, m/z): 287 (M+•, 100); 272
(M+• - CH3, 46.95); 273 (M+• - CH2, 7.28); 256 (M+• - CH3O,
19.53). HRMS: calcd for C16H17NO4 287.1158, found 287.1157.
N-{5-[(Benzofuran-2-carboxyl)amino]-1H-indol-2-carboxyl}-1-
chloromethyl-1,2-dihydro-5-hydroxy-7,8,9-trimethoxybenzo[e]in-
dole (21). A current of gaseous HCl was passed during 30 min
through a solution of cyclopropabenzindole 7 (72 mg, 0.25
mmol) in 20 mL of dry EtOAc. The solvent was removed in
vacuo, and the crude chlorophenol 20 was dissolved in 20 mL
of dry DMF. The acid 6 (214 mg, 0.67 mmol) and EDC · HCl
(173 mg, 0.90 mmol) were added, and the resulting mixture was
stirred at room temperature during 21 h. Water was added, and
the resulting mixture was extracted with CH2Cl2 (3 × 30 mL).
The collected organic phases were dried (Na2SO4) and concen-
trated. The resulting oil was purified by column chromatography
in silica (10 × 1 cm L), delivering compound 21 as a white
solid possessing very low solubility, which could be purified
further by washing with EtOAc. This results in 76 mg of 21,
obtained in 50% overall yield from 7. Rf: 0.63 (toluene/acetone/
Experimental Section
3,4,5-Trimethoxybenzaldehyde (10) was purchased from com-
mercial sources. Methyl 1-methoxymethyl-5-tosylmethyl-1H-
pyrrole-3-carboxylate15 (11), methyl N-methoxymethyl-5-tosyloxy-
7,8,9-trimethoxybenzo[e]indolecarboxylate16(8),and5-[(benzofuran-
2-carbonyl)amino]-1H-indole-2-carboxylic acid17 (6) were prepared
according to published procedures.
Preparation of Key Compounds. N-Acetyl-1-acetoxymethyl-
5-tosyloxy-7,8,9-trimethoxy-1,2-dihydro-3H-benzo[e]indole (17).
A mixture of benzoindole 16 (97 mg, 0.20 mmol) and NaBH3CN
(126 mg, 2.00 mmol) in 2.4 mL of trifluoroacetic acid was stirred
at -5 °C under argon during 20 min. Aqueous sodium hydroxide
(10%, 15 mL) was added, and the resulting mixture was extracted
with CH2Cl2 (3 × 25 mL). The solvent was removed in vacuo from
the collected organic phases, and the residue was dissolved in 5
mL of dry THF. LiAlH4 (70 mg, 1.84 mmol) was added, and the
resulting mixture was stirred for 15 min at room temperature. EtOAc
(10 mL) and 10% NaOH (15 mL) were added, and the resulting
mixture was extracted with CH2Cl2 (3 × 25 mL). The solvent was
removed in vacuo from the collected organic phases, and the residue
was treated with Ac2O (23 mmol, 2.2 mL) and pyridine (27 mmol,
2.2 mL). After 5 h at room temperature, 10% HCl (15 mL) was
added, and the mixture was extracted with CH2Cl2 (3 × 25 mL).
The solvent was removed in vacuo, and the crude was purified by
column chromatography in silica (10 × 1 cm L), delivering 71
mg (65%) of acetate 17 as a white solid. Mp: 224 °C (CH2Cl2). Rf:
1
acetic acid (50:50:1)). H NMR (DMSO, 250 MHz) δ: 11.7 (s,
1H); 10.52 (s, 1H); 8.26 (s, 1H); 7.97 (d, J ) 6.9 Hz, 1H); 7.79
(m, 3H); 7.65 (d, J ) 8.9 Hz, 1H); 7.52 (d, J ) 8.4 Hz, 2H);
7.39 (d, J ) 7.7 Hz, 1H); 7.35 (s, 1H); 7.22 (s, 1H); 4.73 (t, J
) 10.2 Hz, 1H); 4.57 (d, J ) 10.5 Hz, 1H); 4.13 (m, 1H); 3.98
(s, 3H); 3.91 (s, 3H); 3.88 (s, 3H); 3.6 (t, J ) 10.0 Hz, 1H). 13
C
1
0.12 (EtOAc/hexane (1:1)). H NMR (CDCl3, 400 MHz) δ: 8.15
NMR (DMSO, 62.8 MHz) δ: 160.7 (C); 157.2 (C); 155.1 (C);
153.6 (C); 151.5 (C); 149.9 (C); 148.0 (C); 143.0 (C); 141.8
(C); 134.2 (C); 132.4 (C); 131.7 (C); 127.9 (C); 127.7 (C); 127.6
(CH); 124.4 (CH); 123.4 (CH); 121.7 (C); 120.4 (C); 120.1 (CH);
114.1 (CH); 113.9 (C); 112.8 (CH); 112.5 (CH); 110.7 (CH);
106.1 (CH); 101.0 (CH); 99.4 (CH); 62.1 (CH3); 61.3 (CH3);
56.3 (CH3); 55.3 (CH2); 49.1 (CH2); 44.5 (CH). MS (FAB+,
m/z): 625 (M+•, 19.73); 323 (left fragment, 12.42); 145 (right
fragment, 22.96); 131 (central fragment, 6.14); HRMS: calcd
(s, 1H); 7.84 (d, J ) 8.1 Hz, 2H); 7.34 (d, J ) 8.1 Hz, 2H); 7.08
(s, 1H) 4.40 (dd, J ) 10.5 and 3.2 Hz, 1H); 4.08 (m, 3H); 4.00 (s,
3H); 3.91 (s, 3H); 3.87 (s, 3H); 3.68 (m, 1H); 2.44 (s, 3H); 2.22
(d, J ) 6,9 Hz, 3H); 2.03 (s, 3H). 13C NMR (CDCl3, 100 MHz) δ:
171.4 (C); 168.9 (C); 152.8 (C); 148.7 (C); 145.9 (C); 145.8 (C);
140.1 (C); 130.4 (CH); 128.8 (CH); 122.9 (C); 122.6 (C); 121.0
(C); 110.7 (CH); 98.2 (CH); 66.9 (CH2); 61.7 (CH); 61.4 (CH3);
56.1 (CH3); 53.3 (CH2); 41.6 (CH3); 24.6 (CH3); 22.1 (CH3); 21.3
(CH3). MS (EI, 75 eV, m/z): 543 (M+•, 26.31); 470 (M+• - CH2,
7.20); 329 (M+• - OTs - Ac, 21.07). Anal. Calcd for C27H29O9NS:
C, 59.65; H, 5.37; N, 2.57; S, 5.89. Found: C, 59.95; H, 5.71; N,
2.50; S, 5.53.
for C34H28ClN3O7 625.1616, found 625.1595. UV (nm, λmax
,
CH3CN): 303.
N-{5-[(Benzofuran-2-carbonyl)amino]-1H-indole-2-carboxyl}-
1,2,9,9a-tetrahydro-4-oxo-6,7,8-trimethoxybenzo[e]cyclopro-
pa[c]indole (5). A 1 M solution of TBAF (63 µL, 0.06 mmol) in
THF was added over a solution of silyl ether 22 (20 mg, 0.03 mmol)
in dry CH2Cl2 (2 mL). The resulting solution was stirred at room
temperature under argon during 20 min. The solvent was removed
at the rotatory evaporator and the resulting crude was purified by
column chromatography in silica (5 × 1.5 cm L) delivering 10
mg (66%) of compund 5 as a white solid. M.p: >250 °C (EtOAc/
hexane). Rf: 0.39 (EtOAc). 1H NMR (DMSO, 500 MHz) δ: 11.83
(s, 1H); 10.47 (s, 1H); 8.21 (s, 1H); 7.82 (d, J ) 7.8 Hz, 1H); 7.75
(s, 1H); 7.72 (d, J ) 8.3 Hz, 1H); 7.62 (d, J ) 8.9 Hz, 1H); 7.48
(m, 2H); 7.44 (s, 1H); 7.36 (t, J ) 8.5 Hz, 1H); 7.24 (s, 1H); 6.97
(s, 1H); 4.60 (dd, J ) 10.2 and 5 Hz, 1H); 4.45 (d, J ) 10 Hz,
1H); 3.88 (s, 3H); 3.87 (s, 3H); 3.82 (s, 3H); 1.96 (m, 2H). 13C
NMR (DMSO, 125 MHz) δ: 183.5 (C); 162.2 (C); 161.6 (C); 156.5
(C); 154.4 (C); 152.1 (C); 149.1 (C); 145.1 (C); 134.0 (C); 131.3
(C); 130.2 (C); 128.5 (C); 127.2 (C); 127.0 (CH); 126.8 (C); 126.0
(C); 123.8 (CH); 122.8 (CH); 120.1 (CH); 113.5 (CH); 112.4 (CH);
111.9 (CH); 110.2 (CH); 109.5 (CH); 107.2 (CH); 104.2 (CH);
102.5 (C); 61.6 (CH3); 60.5 (CH3); 55.8 (CH3); 54.2 (CH2); 30.7
4-Oxo-1,2,9,9a-tetrahydro-6,7,8-trimethoxybenzo[e]cyclopro-
pa[c]indole (7). To a suspension of phenol 18 (211 mg, 0.6 mmol)
and Ph3P (231 mg, 0.88 mmol) in CH2Cl2 (20 mL) was added 0.1
mL (0.79 mmol) of DEAD. After 17 h of stirring at rt under argon,
the solvent was removed and the resulting crude was purified by
column chromatography in silica (10 × 1.5 cm L), providing a
mixture of cyclopropabenzindol 19 and triphenylphosphine oxide.
This mixture was dissolved in methanol (20 mL). A solution of
NaOMe in MeOH (1.5 M, 2 mL), was added and the resulting
(13) (a) Boger, D. L.; Coleman, R. S.; Invergo, B. J. Org. Chem. 1987, 52,
1521. (b) Boger, D. L.; Coleman, R. S. J. Am. Chem. Soc. 1987, 109, 2717. (c)
Kelly, R. C.; Gebhard, I.; Wicnienski, N.; Aristoff, P. A.; Johnson, P. D.; Martin,
D. G. J. Am. Chem. Soc. 1987, 109, 6837. (d) Boger, D. L.; Invergo, B.; Coleman,
R. S.; Zarrinmayeh, H.; Kitos, P. A.; Thompson, S. C.; Leong, T.; McLaughlin,
L. W. Chem.-Biol. Interact. 1990, 72, 29.
(14) (a) Boger, D. L.; Ishizaki, T.; Zarrinmayeh, H.; Kitos, P. A.; Suntornwat,
O. J. Org. Chem. 1990, 55, 4499. (b) Wang, Y.; Gupta, R.; Huang, L.; Lown,
J. W. J. Med. Chem. 1993, 26, 4172.
(15) See ref 7.
(16) See ref 5.
(17) Warpehoski, M. A. Tetrahedron Lett. 1986, 27, 4103.
J. Org. Chem. Vol. 74, No. 8, 2009 3205