Regiospecific synthesis of mono-n-substituted indolopyrrolocarbazoles

Article abstract of DOI:10.1021/ol051550a

(Chemical Equation Presented) Two complementary and efficient strategies have been developed for the regiospecific synthesis of unsymmetrical indolopyrrolocarbazoles (IPCs) mono-N-substituted with a pentacycle. A halogen in position 2 of the intermediate bisindolylmaleimides 3a-e allows a selective Mitsunobu coupling by exploiting the increased acidity of the 2-chloro-substituted indole nitrogen. It also promotes an easier cyclization of bisindolylmaleimides 4a-e and 7b-e to IPCs. Alkylation of the 2-unsubstituted indole-3-carboxamides 2a,b and further processing to the corresponding IPCs gives access to the opposite regioisomers.

Full text of DOI:10.1021/ol051550a

ORGANIC
LETTERS
2
005
Vol. 7, No. 21
573-4576
Regiospecific Synthesis of
Mono-N-substituted
4
Indolopyrrolocarbazoles
†
Wolfgang Fro
1
hner, Barbara Monse, Tobias M. Braxmeier, Laura Casiraghi,
‡
Heidi Sahag u´ n,* and Pierfausto Seneci
Chemistry Department, Sirenade Pharmaceuticals AG, Am Klopferspitz 19a,
D-82152 Martinsried, Germany
sahagun@sirenade.biz
Received July 1, 2005
ABSTRACT
Two complementary and efficient strategies have been developed for the regiospecific synthesis of unsymmetrical indolopyrrolocarbazoles
IPCs) mono-N-substituted with a pentacycle. A halogen in position 2 of the intermediate bisindolylmaleimides 3a e allows a selective Mitsunobu
coupling by exploiting the increased acidity of the 2-chloro-substituted indole nitrogen. It also promotes an easier cyclization of
bisindolylmaleimides 4a e and 7b e to IPCs. Alkylation of the 2-unsubstituted indole-3-carboxamides 2a,b and further processing to the
(
−
−
−
corresponding IPCs gives access to the opposite regioisomers.
The synthesis of indolopyrrolocarbazole (IPC) glycosides
constitutes a hot topic for the chemistry community due to
the wide range of biological activities covered by the
representative natural products of this family (cf. Figure 1).
Monoglycosidated IPCs, such as rebeccamycin isolated in
1
a
1
985, have shown remarkable antiproliferative properties
1
and inhibitory potency toward topoisomerase I. A derivative
of rebeccamycin, NB-506 (L-753000), and recently BMS-
50749 have entered clinical trials as antitumoral agents,
and a third one, ED-749 (J-107088), is currently in clinical
2
3
2
4
†
Current address: Jado Technologies, Tatzberg 47-51, 01307 Dresden,
Germany.
‡
Current address: Department of Organic and Industrial Chemistry,
Figure 1. Representative indolopyrrolocarbazoles (IPC).
University of Milan, Via Venezian 21, 20100 Milan, Italy.
(1) (a) Nettleton, D. E.; Doyle, T. W.; Krishnan, B.; Matsumoto, G. K.;
Clardy, J. Tetrahedron Lett. 1985, 26, 4011. (b) Bush, J. A.; Long, B. H.;
Catino, J. J.; Bradner, W. T.; Tomita, K. J. Antibiot. 1987, 40, 668. (c)
Prudhomme, M. Curr. Med. Chem. 2000, 7, 1189.
phase III for the treatment of solid tumors and glioblastoma.
In contrast, N,N′-bis-substituted IPCs, such as staurosporine
(2) Ohe, Y.; Tanigawara, Y.; Fujii, H.; Ohtsu, T.; Wakita, H.; Igarashi,
or K
kinases.
-
252A, exhibit potent inhibition of various protein
T.; Minami, H.; Educhi, K.; Shinkai, T.; Tamura, T.; Kunotoh, H.; Saijo,
N.; Okada, K.; Ogino, H.; Sasaki, Y. Proc. ACSO 1997, 16, 199a.
5
,6
(3) Saulnier, M. G.; Balasubramanian, B. N.; Long, B. H.; Frennesson,
We focused our attention on the synthesis of rebeccamy-
cin-like IPC derivatives with an unsymmetrical substitution
D. B.; Ruedinger, E.; Zimmermann, K.; Eummer, J. T.; Laurent, D. R. St.;
Stoffan, K. M.; Naidu, B. N.; Mahler, M.; Beaulieu, F.; Bachand, C.; Lee,
F. Y.; Fairchild, C. R.; Stadnick, L. K.; Rose, W. C.; Solomon, C.; Wong,
H.; Martel, A.; Wright, J. J.; Kramer, R.; Langley, D. R.; Vyas, D. M. J.
Med. Chem. 2005, 48, 2258-2261.
(4) Long, B. H.; Balasubramanian, B. N. Expert Opin. Ther. Pat. 2000,
10, 635.
1
0.1021/ol051550a CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/13/2005

Scheme 1. Comparison of Strategies
pattern, wherein the carbohydrate moiety was replaced by a
1, eq 2), which allows (1) a regioselective Mitsunobu reaction
for the introduction of an allylic cyclopentenol in an
unsymmetrical and completely deprotected aglycon and (2)
leads to easier non-oxidative light-promoted cyclization of
bisindolylmaleimides to IPCs in almost quantitative yield.
pentacyclic hydrocarbon derivative acting as a sugar ana-
logue. Recently, related structures have been published
having also pentacycle rings but related to K-252a and
showing kinase inhibition activity.7
Two major challenges which have to be overcome during
the synthesis of this class of compounds are (1) the relative
low reactivity of the indole nitrogens within the aromatic
system compared to the imidic nitrogen and (2) the selective
functionalization of only one indole nitrogen in unsym-
metrical aglycons.
Scheme 2. Synthesis of Methyl 2-Chloroindole-3-glyoxylates
Different approaches have been published for the synthesis
of unsymmetrical IPCs, by condensation of two 3-substituted
8
indole derivatives or by Grignard reactions between two
9
indole units and a protected maleimide. Oxidation of the
intermediate products (bisindolylmaleimides, indole-indo-
lines) to IPCs is mostly conducted with Pd salts or oxidation
reagents such as DDQ. In some of these approaches, a
protection strategy is required to achieve specific mono-
functionalization of only one indole nitrogen.6
1
2
Using Bergman’s synthesis (Scheme 2), oxindoles were
converted to the corresponding methyl 2-chloroindole-3-
glyoxylates 1a-c. All intermediates and products were
isolated by precipitation as stable solids.
,9,10
Our synthetic approach is partially inspired by the strategy
The starting materials oxindole and its 6-chloro derivative
are commercially available. 5-Bromooxindole was obtained
in 77% yield by simple bromination of commercial oxindole
2
and KBr in boiling water.
Intermolecular Perkin-type condensation of methyl 2-chloro-
11
proposed by Faul et al. who reported an improved synthesis
of arcyriarubin A (bisindolylmaleimide) starting from methyl
indole-3-glyoxylate and indole-3-acetamide (Scheme 1, eq 1).
1
3
using Br
Our fundamental modification was the introduction of a
halogen atom in position 2 of the glyoxylic indole (Scheme
14
15
indole-3-glyoxylates 1a-c with indole-3-acetamides 2a,b
in the presence of KOtBu in THF provided, after treatment
with HCl, unsymmetrical bisindolylmaleimides 3a-e in
yields between 50 and 85% (Scheme 3) (3d was only isolated
in 14% yield due to the low solubility of the product).
Subsequently, under classical Mitsunobu conditions we
were able to functionalize regiospecifically the 2-chloro-
substituted indole nitrogen due to its increased acidity
(
5) (a) Tamaoki, T.; Nomoto, H.; Takahashi, I.; Kato, Y.; Morimoto,
M.; Tomita, F. Biochem. Biophys. Res. Commun. 1986, 135, 397. (b)
Oikawa, T.; Shimamura, M.; Asino, H.; Nakamura, O.; Nanayasu, T.;
Morita, I.; Murata, S. I. J. Antibiot. 1992, 45, 1155.
(6) (a) Kase, H.; Iwahashi, K.; Matsuda, Y. J. Antibiot. 1986, 39, 1059.
(
b) Kase, H.; Iwahashi, K.; Nakanishi, S.; Matsuda, Y.; Yamada, K.;
Takasashi, M.; Murakata, C.; Sato, A.; Kaneko, M. Biochem. Biophys. Res.
Commun. 1987, 142, 436.
(
7) Moffat, D.; Nichols, C. J.; Riley, D. A.; Simpkins, N. S. Org. Biolmol.
Chem. 2005, 3, 2953-2975.
8) Faul, M. M.; Winneroski, L. L.; Krumrich, C. A. J. Org. Chem. 1999,
4, 2465.
9) (a) Ohkubo, M.; Nishimura, T.; Jona, H.; Homna, T., Ito, S.;
1
6
induced by the halogen. Thus, reaction of 3a-e with an
(
17
allylic cyclopentenol provided the corresponding bisin-
6
dolylmaleimides 4a-e. Although major products were
always 4a-e as seen by TLC analysis, the compounds were
only isolated in modest yields (31-45%) as two subsequent
(
Morishima, H. Tetrahedron 1997, 53, 5937. (b) Chisholm, J. D.; Van
Vranken, D. L. J. Org. Chem. 2000, 65, 7541. (c) Brenner, M.; Rexhausen,
H.; Steffan, B.; Steglich, W. Tetrahedron 1988, 44, 2887.
(
10) (a) Kaneko, T.; Wong, H.; Okamoto, K. T.; Clardy, J. Tetrahedron
Lett. 1985, 26, 4015. (b) Gallant, M.; Link, J. T.; Danishefsky, S. J. J. Org.
Chem. 1993, 58, 343. (c) Link, J. T.; Raghavan, S.; Danishefsky S. J. J.
Am. Chem. Soc. 1995, 117, 552. (d) Link, J: T.; Raghavan, S.; Gallant,
M.; Danishefsky, S. J.; Chou, T. C.; Ballas, L. M. J. Am. Chem. Soc. 1996,
(12) Bergman, J.; Carlsson, R.; Sjoberg B. J. Heterocycl. Chem. 1977,
14, 1123.
(13) Sumpter, W. C.; Miller, M.; Hendrick, L. N. J. Am. Chem. Soc.
1945, 67, 1656.
1
18, 2825.
(14) For preparation of 2-cholor-3-glyoxylates see ref 12.
(15) For preparation of indole-3-acetamides see ref 8.
(16) Porter, W. L.; Thiman, K. V. Phytochemistry 1965, 4, 229.
(11) Faul, M. M.; Winneroski, L. L.; Krumrich, C. A. J. Org. Chem.
1
998, 63, 3, 6053.
4574
Org. Lett., Vol. 7, No. 21, 2005

Scheme 3. Synthesis of Compounds 5a-e (Route A)
Scheme 4. Synthesis of Compounds 8b-e (Route B)
column chromatographies were necessary to eliminate small
quantities of byproducts (5-10% of starting material and
bisalkylated product), hydrazine dicarboxylate, and triph-
enylphosphine-related substances.
This regioselectivity, in contrast, could not be obtained in
our hands on arcyriarubin A, since the two indole nitrogens
are undifferentiated. Instead, mixtures of mono-, bis-, and
trisalkylated products resulted.
1
at the R -substituted indole were obtained with complete
regiocontrol (Table 1, entries 1-5).
This new mild method proved to be very useful for our
purposes as some strategies from the literature were not
suited for our targets. For example, we observed that the
allylic pentacycle was lost when treated with acids (TFA/
anisole or AlCl
or palladium salts (oxidation step).
3
used for PMB deprotection of the imide)
9
,10
In our strategy, the enhanced reactivity of the chloro-
substituted heterocycle directs the Mitsunobu alkylation
selectively to the indole. In addition, unlike other synthe-
Bisindolylmaleimide 3a was also submitted to light-
induced cyclization in which case arcyriaflavin A was
obtained in 95% yield. The total yield of the synthesis of
this natural product was 40% starting from oxindole.
A second strategy was elaborated for the synthesis of the
opposite regioisomers as shown in Scheme 4. In this case,
the carbacycle unit was introduced at an earlier stage by
direct alkylation of indole-3-acetamides 2a,b using the
cyclopentene mesylate. This reaction provides a mixture of
cis and trans products, from which the cis isomers were
isolated as the major product in around 50% yield. Subse-
quent condensation with methyl 2-chloroindole-3-glyoxylates
9
,10,18
ses,
the method allows also the presence of all three
unprotected nitrogens on the bisindolylmaleimide during the
alkylation step.
Finally, subsequent cyclization of the monofunctionalized
bisindolylmaleimides 4a-e to IPCs 5a-e was significantly
facilitated by the presence of the 2-chloro substituent. Thus,
compounds 4a-e underwent smooth cyclization to the final
IPCs 5a-e in 91-99% yields by simple irradiation with a
1
a-c provided the corresponding functionalized bisindolyl-
Table 1. Yields of Compounds 5a-e and 8b-e
maleimides 7b-e in around 50% yield, representing the
regioisomers of 4b-e (7d was only isolated in 22% yield
due to low solubility of the product).
Cyclization to the complementary decorated IPCs was
achieved as described before in very good yields (90-98%),
and compounds 8b-e were obtained in three steps as single
isomers in moderate overall yields (Table 1, entries 6-9).
a
c
entry IPC route
R1
R2
yield (%) yield (%)
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
8b
8c
8d
8e
A
A
A
A
A
B
B
B
B
H
H
H
H
15
32
29
5
15
22
23
11
24
31
38
45
35
35
NA
NA
NA
NA
5-Br
6-Cl
H
b
b
5-OMe
5-Br 5-OMe
5-Br
6-Cl
H
H
H
5-OMe
(17) Preparation of trans-4-(tert-butyldimethylsilanyloxy)cyclopent-2-
enol: (a) Crandall, J. K.; Banks, D. B.; Colyer, R. A.; Watkins, R. J.;
Arrington, J. P. J. Org. Chem. 1968, 33, 423. (b) Deardorff, D. R.; Myles,
D. C. Org. Synth. 1989, 67, 114. (c) Korach, M.; Nielson, D. R.; Rideout,
W. H. Organic Syntheses; Wiley: New York, 1973; Collect. Vol. V, p
5-Br 5-OMe
a
b
Overall yield according to Schemes 3 or 4. Decreased yield due to
low solubility of 3d or 7d. Yield for the Mitsunobu reaction to access
intermediates 4.
c
4
14. (d) Deardoff, D. R.; Myles, D. C. Organic Syntheses; Wiley: New
York, 1993; Collect. Vol. VIII, p 13.
18) (a) Onkubo, M.; Kawamoto, H.; Ohno, T.; Nakano, M., Morishima,
(
H. Tetrahedron 1997, 53, 585. (b) Zembower, D. E.; Zhang, H.; Lineswala,
J. P.; Kuffel, M. J.; Aytes, S. A.; Ames, M. M. Bioorg. Med. Chem. Lett.
1999, 9, 145.
strong light source (halogen lamp 1000 W). Usage of
purification procedures is not needed, and products alkylated
Org. Lett., Vol. 7, No. 21, 2005
4575

In conclusion, exploiting the possibility to combine indole-
derived building blocks with different substitution pattern,
the two complementary strategies (routes A and B) allow
the direct regiocontrolled synthesis of N-indole-monosub-
This method should prove to be extremely useful to access
previously unreported members of this important class of
biologically active compounds.
Supporting Information Available: Detailed description
of experimental procedures and analytical data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
stituted IPCs either on the R substituted indole or opposite
to it. Moreover, the presence of a chlorine atom allows a
selective Mitsunobu reaction on an unprotected bisindolyl-
maleimide and affords higher yields for the oxidation step
relative to literature procedures.
OL051550A
4576
Org. Lett., Vol. 7, No. 21, 2005