Photocyclization of tosylstilbenes as a key reaction in the preparation of an analogue of the antitumor agent CC-1065

Article abstract of DOI:10.1021/jo900140t

A photocyclization of tosylstilbenes in the presence of base is used as a key reaction in the synthesis of the CC-1065 analogue 5.

Full text of DOI:10.1021/jo900140t

SCHEME 1. Photochemical Preparation of Phenanthrenes
from Tosylstilbenes
Photocyclization of Tosylstilbenes as a Key
Reaction in the Preparation of an Analogue of
the Antitumor Agent CC-1065
Ana G. Neo,† Antonio Pe´rez, Carmen Lo´pez, Luis Castedo,
and Gabriel Tojo*
Departamento de Qu´ımica Orga´nica y Unidad Asociada al
CSIC, UniVersidad de Santiago de Compostela,
15782 Santiago de Compostela, Spain
SCHEME 2. Retrosynthetic Analysis for the Preparation
of 5
gabriel.tojo@usc.es
ReceiVed January 22, 2009
A photocyclization of tosylstilbenes in the presence of base
is used as a key reaction in the synthesis of the CC-1065
analogue 5.
CC-1065 (1) (Figure 1) is an extremely potent antitumor
antibiotic isolated from a Streptomyces strain,1 which, regret-
tably, possesses no clinical utility due to delayed hepatotoxicity.2
Following the identification of the structural features leading
to hepatotoxicity,3 a substantial number of derivatives with
antitumor activity have been prepared.4
a tosyl group on the central double bond. Thus, we showed
that the irradiation of tosylstilbenes (2) causes a cyclization
leading to a tosyldihydrophenantrene (3) that loses p-toluen-
sulfinic acid in contact with base, resulting in aromatization to
a phenanthrene (4) (Scheme 1).
The synthesis of the CC-1065 analogue 5 is based in this
phenanthrene synthesis (Scheme 2). Compound 5 presents a
methoxy group closely positioned to the alkylating cyclopropane
unit. Hopefully, the steric hindrance posed by this group would
modulate in a biologically useful way the properties of
compound 5.
Compound 7 can be obtained from phenanthrenoid 8, which,
in turn, can be derived from stilbenoid 9. This stilbenoid 9 can
(3) See: Wang, Y.; Li, L.; Ye, W.; Tian, Z.; Jiang, W.; Wang, H.; Wright,
S. C.; Larrick, J. W. J. Med. Chem. 2003, 46, 634, and references cited therein.
(4) (a) Boger, D. L.; Coleman, R. S. J. Am. Chem. Soc. 1988, 110, 4796. (b)
Mitchell, M. A.; Kelly, R. C.; Wicnienski, N. A.; Hatzenbbler, T.; Willians,
M. G.; Petzold, G. L.; Slightom, J. L.; Siemieniak, D. K. J. Am. Chem. Soc.
1991, 113, 8994. (c) Boger, D. L.; Boyce, C. W.; Garbaccio, R. M.; Goldberg,
J. A. Chem. ReV. 1997, 97, 787. (d) Boger, D. L.; Brunette, S. R.; Garbaccio,
R. M. J. Org. Chem. 2001, 66, 5163. (e) Boger, D. L.; Schmitt, H. W.; Fink,
B. E.; Hedrick, M. P. J. Org. Chem. 2001, 66, 6654. (f) Tietze, L. F.; Herzig,
T.; Fenerstein, T.; Schuberth, I. Eur. J. Org. Chem. 2002, 1634. (g) Wang, Y.;
Yuan, H.; Wright, S. C.; Wang, H.; Larrick, J. W. Bioorg. Med. Chem. 2003,
11, 1569.
(5) Almeida, J. F.; Castedo, L.; Ferna´ndez, D.; Neo, A. G.; Romero, V.;
Tojo, G. Org. Lett. 2003, 5, 4939.
(6) For recent phenanthrene preparations by irradiation in presence of base
of stilbenes possesing good-leaving groups attached to an aromatic ring, see:
(a) Kimatura, T.; Kobayashi, S.; Taniguchi, H. J. Org. Chem. 1990, 55, 1801.
(b) Kitamura, T.; Kabashima, T.; Taniguchi, H. J. Org. Chem. 1991, 56, 3739.
FIGURE 1. Structure of alkaloid CC-1065.
In a previous work,5 we described a synthesis of phenan-
threnes and phenanthrenoids involving irradiation with UV light,
in the presence of base,6 of stilbenes and stilbenoids containing
† Current address: Departamento de Qu´ımica Orga´nica e Inorga´nica, Uni-
versidad de Extremadura, 10071-Ca´ceres, Spain.
(1) (a) Hanka, L. J.; Dietz, A.; Gerpheide, S. A.; Kuentzel, S. L.; Martin,
D. G. J. Antibiot. 1978, 31, 1211. (b) Mart´ın, D. G.; Biles, C.; Gerpheide, S. A.;
Hanka, L. J.; Krueger, W. C.; McGroven, J. P.; Mizsak, S. A.; Neil, G. L.;
Stewart, J. C.; Visser, J. J. J. Antibiot. 1981, 34, 1119.
(2) (a) McGovern, J. P.; Clarke, G. L.; Pratt, E. A.; DeKoning, T. F. J.
Antibiot. 1984, 37, 63. (b) Iida, H.; Lown, J. W. Recent. Res. DeV. Synth. Org.
Chem. 1988, 1, 17, and references cited therein.
10.1021/jo900140t CCC: $40.75
Published on Web 03/18/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 3203–3206 3203

SCHEME 3. Preparation of Phenanthrenoid 8
SCHEME 4. Synthesis of CC-1065 Derivative Alkylating
Subunit
SCHEME 5. Synthesis of CC-1065 Analogue 5
be accessed in a convergent way from pyrrole derivative 11
and 3,4,5-trimethoxybenzaldehyde (10).
LDA-induced condensation of sulfone 117 with aldehyde 10
led to alcohol 13 (Scheme 3). Oxidation of alcohol 13 under
Jones conditions8 followed by treatment with tosyl chloride
yielded the key tosylstilbenoid 9. Irradiation with a 450 W
medium pressure mercury lamp of tosylstilbenoid 9 in the
presence of DBU under strictly anhydrous conditions led to a
98% yield of the key phenanthrenoid 8, in which the tosyl group
was lost from the intermediate dihydrophenanthrenoid 15 by a
base-induced elimination.
The removal of the MOM group in benzoindole 8 was
effected in two steps, involving reaction with aqueous formic
acid followed by reaction of the resulting aminal with sodium
hydroxide in wet THF (Scheme 4), leading to compound 16.9
Reduction of benzoindole 16 with NaBH3CN in trifluoroacetic
acid10 led to the corresponding unstable indoline, whose ester
was reduced to alcohol with LiAlH4. Treatment of the alcohol
with acetic anhydride allowed the isolation of the stable
acetylated compound 17. Deprotection of the tosylated phenol
and the alcohol in compound 17 by treatment with KOH led to
benzoindoline 18, which was subjected to an intramolecular
Mitsunobu reaction with DEAD and triphenylphosphine,11
giving the acetylated compound 19. The acetyl group in 19 could
be removed under very mild conditions using sodium methox-
ide12 because the nitrogen atom in the resulting compound 7
belongs to a vinylogous amide.
It is not possible to couple 18 with the central and right parts
because the nitrogen is protected as an amide. The amide could
be hydrolyzed in 18, but it would demand very harsh reaction
conditionsseither acidic or basic. The removal of the acetate
was made under much milder conditions in the cyclized
compound 19, where the leaving group was a nitrogen in the
form of a vinylogous amide. The conjugation of the nitrogen
of amine 7 with the carbonyl group in position 4 impedes the
condensation of amine 7 with the acid 6. Therefore, the amine
7 was treated with gaseous hydrogen chloride (Scheme 5)
leading to the phenol 20, which was condensed in situ with the
acid 6 using EDC13 to give compound 21. Compound 21 is
very insoluble, making the formation of cyclopropane ring not
possible. In variance, the TBDMS-protected compound 22s
whose preparation was possible regardless of the insolubility
(7) Sulfone 11 can be easily prepared using a procedure previously reported
by our group: Castedo, L.; Delamano, J.; Lo´pez, C.; Lo´pez, M. B.; Tojo, G.
Heterocycles 1994, 38, 495.
(8) (a) Bowden, K.; Heilbron, I. M.; Jones, E. R. H.; Weedon, B. C. L.
J. Chem. Soc. 1946, 39. (b) Bowers, A.; Halsall, T. G.; Jones, E. R. H.; Lemin,
A. J. J. Chem. Soc. 1953, 2548.
(9) This two-step deprotection protocol resulted from extensive experimenta-
tion in which other methods failed due to the sensitivity of benzoindole 8 to
acid.
(10) (a) Jones, R. J.; Cava, M. P. J. Chem. Soc., Chem. Commun. 1986, 826.
(b) Rawal, V. H.; Jones, R. J.; Cava, M. P. J. Org. Chem. 1987, 52, 19.
(11) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Magnus, P.; Gallager, T.
J. Chem. Soc., Chem. Commun. 1984, 389.
(12) (a) Magnus, P.; Gallagher, T.; Schultz, J.; Or, Y. S.; Ananthanarayan,
T. P. J. Am. Chem. Soc. 1987, 109, 2706. (b) Bolton, R.; Moody, C. J.; Pass,
M.; Rees, C. W.; Tojo, G. Org. Bio-Org. Chem. 1988, 8, 2491. (c) Castedo, L.;
Delamano, J.; Enjo, J.; Fernández, J.; Gravalos, D. G.; Leis, R.; López, C.;
Marcos, C. F.; Ríos, A.; Tojo, G. J. Am. Chem. Soc. 2001, 123, 5102.
3204 J. Org. Chem. Vol. 74, No. 8, 2009

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

(C); 24.3 (CH); 23.8 (CH2). MS (FAB+, m/z): 588 (M+• - H, 1.11).
Supporting Information Available: General procedure to
obtain compounds 16, 18, and 22, characterization for new
products, and copies of 1H and 13C NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
HRMS: calcd for C34H27N3O7 589.1849, found 589.1858. UV (nm,
λmax, CH3CN): 324, 259.
Acknowledgment. We thank the Spanish Ministry of
Science and Technology (SAF2001-3120) and the Xunta de
Galicia(PGIDIT02RAG20901PRandPGIDIT02PXIC20902PN)
for financial support. A.P. thanks the Spanish Ministry of
Educaction and Science for a predoctoral research grant.
JO900140T
3206 J. Org. Chem. Vol. 74, No. 8, 2009