New synthetic protocols for the preparation of unsymmetrical bisindoles

Article abstract of DOI:10.1021/ol062338p

(Diagram presented) Novel unsymmetrical bisindoles were synthesized by a solvent-free C-C bond-formation reaction under mild conditions. Starting from aziridines or hydroxyl precursors, indoles have been used as C-nucleophiles to form new pharmacologicall

Full text of DOI:10.1021/ol062338p

ORGANIC
LETTERS
2
006
Vol. 8, No. 25
761-5764
New Synthetic Protocols for the
Preparation of Unsymmetrical Bisindoles
5
†
,‡
†
†
†
Hanns Martin Kaiser, Wei Fun Lo, Abdol Majid Riahi, Anke Spannenberg,
†,‡
,†,‡,
Matthias Beller, and Man Kin Tse*
Leibniz-Institut f u¨ r Katalyse e.V. an der UniVersit a¨ t Rostock, Albert-Einstein-Str. 29a,
D-18059 Rostock, Germany, and Center for Life Science Automation (CELISCA),
Friedrich-Barnewitz-Str. 8, D-18119 Rostock-Warnem u¨ nde, Germany
man-kin.tse@catalysis.de
Received September 22, 2006
ABSTRACT
Novel unsymmetrical bisindoles were synthesized by a solvent-free C−C bond-formation reaction under mild conditions. Starting from aziridines
or hydroxyl precursors, indoles have been used as C-nucleophiles to form new pharmacologically interesting bisindoles via an electrophilic
aromatic substitution pathway in good to excellent yields.
During the last two decades, protein kinases were found to
be involved in essential regulatory cellular functions such
as gene expression, cellular proliferation, differentiation,
1
membrane transport, and apoptosis. Staurosporine (1), a
bisindole, has been found as one of the first kinase inhibitors
2
in nanomolar concentrations. In addition, various small
3
molecular kinase inhibitors are known. Among them,
4
5
Hymenialdisine (HMD) (2) and annulated derivatives 3
Figure 1) have been found to inhibit a number of different
(
kinases very selectively. Additionally, compounds 2 and 3
prevent the production of cytokines.6
We have been interested in the application of catalytic
reactions for the synthesis of potential pharmaceuticals for
Figure 1. Structures of Staurosporine (1), Hymenialdisine (HMD)
(2), and HMD analogues 3.
†
Leibniz-Institut f u¨ r Katalyse e.V. an der Universit a¨ t Rostock.
Center for Life Science Automation (CELISCA).
‡
7
(
1) Bridges, A. J. Chem. ReV. 2001, 101, 2541-2571.
some time. As a starting point for the development of new
bioactive kinase inhibitors, we decided to prepare a small
(2) Tamaoki, T.; Nomoto, H.; Takahashi, I.; Kato, Y.; Morimoto, M.;
Tomita, F. Biochem. Biophys. Res. Commun. 1986, 135, 397-402.
3) Huwe, A.; Mazitschek, R.; Giannis, A. Angew. Chem., Int. Ed. 2003,
2, 2122-2138.
4) (a) Cimino, G.; De Rosa, S.; De Stefano, S.; Mazzarella, L.; Puliti,
(
4
(5) Wan, Y.; Hur, W.; Cho, C. Y.; Liu, Y.; Adrian, F. J.; Lozach, O.;
Bach, S.; Mayer, T.; Fabbro, D.; Meijer, L.; Gray, N. S. Chem. Biol. 2004,
11, 247-259.
(6) Sharma, V.; Lansdell, V. A.; Jin, G.; Tepe, J. J. J. Med. Chem. 2004,
47, 3700-3703.
(
R.; Sodano, G. Tetrahedron Lett. 1982, 23, 767-768. (b) Kitagawa, I.;
Kobayashi, M.; Kitanaka, K.; Kido, M.; Kyoguku, Y. Chem. Pharm. Bull.
983, 31, 2321-2328.
1
1
0.1021/ol062338p CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/14/2006

compound library of unsymmetrical bisindoles. As a part of
this project, we developed a solvent-free, efficient, and easy
to handle diversification strategy for annulated HMD-type
bisindoles via a C-C bond-formation reaction on activated
silica under mild reaction conditions starting from aziridines
or hydroxyl compounds.
it should be possible to perform these reactions highly regio-
19
and stereoselectively. For aziridination of olefins, a number
of different metal-catalyzed nitrene transfer methods with
copper, rhodium, ruthenium, iron, cobalt, manganese, silver,
20
and gold catalysts were described. With respect to synthetic
application, we decided to perform the bromine-catalyzed
aziridination developed by Sharpless and co-workers be-
cause this protocol does not require an excess of olefin
In the past, different synthetic strategies have been
developed for the synthesis of the pyrrolo[2,3-c]azepine motif
of HMD. The first total synthesis of HMD (2) was published
2
1
(Scheme 2).
8
by Annoura; later, Horne introduced another synthetic
9
strategy. Recently, a new total synthesis was introduced by
10
Papeo. Annulated HMD derivatives usually were prepared
via the azepino[3,4-b]indole-1,5-dione (5) intermediate or
the corresponding alcohol (()-6 and subsequent attachment
Scheme 2. Bromine-Catalyzed Aziridination of 7
5
of the imidazole heterocycle. Azepino-indole 5 is usually
synthesized via intramolecular cyclization reactions with
11
2 5
MsOH/P O . Also, protocols employing ring-closing meta-
1
2
13
thesis and polyphosphoric acid were introduced so far.
It has been shown that the kinase inhibiting activities of
annulated HMDs 3 vary very much when other heterocycles
5
instead of imidazole are introduced. Hence, we aimed to
develop a general and easy manageable preparation of
unsymmetrical HMD-type bisindoles. On the basis of our
experience on oxidation methods,14 we planned to use
different oxidation reactions as a toolbox for diversity-
15
To our delight, the aziridination of 7 proceeded smoothly
to give (()-8 in good yield (78%). In contrast to the reported
literature conditions, the reaction is favorably carried out
oriented synthesis. Until now, relatively little use has been
made applying oxidation methodologies for this purpose. The
starting material 7 was synthesized in a one-pot elimination-
5
protection procedure from (()-6 (Scheme 1). Boc-protecting
(7) (a) Kumar, K.; Michalik, D.; Castro, I. G.; Tillack, A.; Zapf, A.;
Arlt, M.; Heinrich, T.; B o¨ ttcher, H.; Beller, M. Chem.-Eur. J. 2004, 10,
7
46-757. (b) Michalik, D.; Kumar, K.; Zapf, A.; Tillack, A.; Arlt, M.;
Heinrich, T.; Beller, M. Tetrahedron Lett. 2004, 45, 2057-2061. (c) Tewari,
Scheme 1. Synthesis of Intermediates (()-6 and 7
A.; Hein, M.; Zapf, A.; Beller, M. Tetrahedron Lett. 2004, 45, 7703-7707.
(d) Khedkar, V.; Tillack, A.; Michalik, M.; Beller, M. Tetrahedron 2005,
6
1, 7622-7631. (e) Neumann, H.; Str u¨ bing, D.; Lalk, M.; Klaus, S.; H u¨ bner,
S.; Spannenberg, A.; Lindequist, U.; Beller, M. Org. Biomol. Chem. 2006,
4
, 1365-1375.
(
8) Annoura, H.; Tatsuoka, T. Tetrahedron Lett. 1995, 36, 413-416.
(9) (a) Xu, Y.-Z.; Yakushijin, K.; Horne, D. A. J. Org. Chem. 1997, 62,
4
56-464. (b) Sosa, A. C. B.; Yakushijin, K.; Horne, D. A. J. Org. Chem.
2000, 65, 610-611.
(10) Papeo, G.; Posteri, H.; Borghi, D.; Varasi, M. Org. Lett. 2005, 7,
5
641-5644.
(
11) Cho, H.; Matsuki, S. Heterocycles 1996, 43, 127-131.
(12) Chacun-Lef e` vre, L.; B e´ n e´ teau, V.; Joseph, B.; M e´ rour, J.-Y.
Tetrahedron 2002, 58, 10181-10188.
13) Suzuki, H.; Shinpo, K.; Yamazaki, T.; Niwa, S.; Yokoyama, Y.;
Murakami, Y. Heterocycles 1996, 42, 83-86.
14) For recent publications in this area, see: (a) Tse, M. K.; D o¨ bler,
(
(
C.; Bhor, S.; Klawonn, M.; M a¨ gerlein, W.; Hugl, H.; Beller, M. Angew.
Chem., Int. Ed. 2004, 43, 5255-5260. (b) Tse, M. K.; Bhor, S.; Klawonn,
M.; Anilkumar, G.; Jiao, H.; D o¨ bler, C.; Spannenberg, A.; M a¨ gerlein, W.;
Hugl, H.; Beller, M. Chem.-Eur. J. 2006, 12, 1855-1874. (c) Tse, M. K.;
Bhor, S.; Klawonn, M.; Anilkumar, G.; Jiao, H.; Spannenberg, A.; D o¨ bler,
C.; M a¨ gerlein, W.; Hugl, H.; Beller, M. Chem.-Eur. J. 2006, 12, 1875-
1
888. (d) Tse, M. K.; Klawonn, M.; Bhor, S.; D o¨ bler, C.; Anilkumar, G.;
Hugl, H.; M a¨ gerlein, W.; Beller, M. Org. Lett. 2005, 7, 987-990.
15) (a) Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004,
(
groups were introduced to obtain a more stable and storable
alkene, which smoothly reacts in the subsequent aziridination
reaction.
4
3, 46-58. (b) Schreiber, S. L. Science 2000, 287, 1964-1969. (c) Nicolaou,
K. C.; Pfefferkorn, J. A.; Roecker, A. J.; Cao, G.-Q.; Barluenga, S.; Mitchell,
H. J. J. Am. Chem. Soc. 2000, 122, 9939-9953.
(16) (a) Herrmann, W. A.; Fischer, R. W.; Marz, D. W. Angew. Chem.,
Although initial exploratory experiments employing stan-
Int. Ed. 1991, 30, 1638-1641. (b) Rudolph, J.; Reddey, K. L.; Chiang, J.
P.; Sharpless, K. B. J. Am. Chem. Soc. 1997, 119, 6189-6190.
1
6
dard epoxidation methods such as m-CPBA or MTO were
(17) For a review, see: Tanner, D. Angew. Chem., Int. Ed. 1994, 33,
not successful, we turned our interest to the aziridination of
5
99-619.
18) For reviews, see: (a) Hu, X. E. Tetrahedron 2004, 60, 2701-2743.
b) Stamm, H. J. Prakt. Chem. 1999, 341, 319-331.
19) For a review, see: Sweeney, J. B. Chem. Soc. ReV. 2002, 31, 247-
258.
17
(
olefin 7. It is well documented that N-arylsulfonylaziridines
(
1
8
react with C, O, S, N, halogen, or hydrogen nucleophiles
in the presence of a base, an acid, or a Lewis acid. In general,
(
5762
Org. Lett., Vol. 8, No. 25, 2006

and the ring-opening product of the formed aziridine with
2
2
Table 1. Ring-Opening Reactions of (()-8a
the amide salt. Next, we attempted the direct arylation of
various indoles using (()-8 as the key building block in the
presence of acidic heterogeneous catalysts such as clay or
silica. The arylations took place highly regioselectively at
23
2
4
the benzylic position of (()-8 applying Hudlicky’s protocol
24a
of solvent-free conditions on silica (Table 1). All reactions
ran overnight at 70 °C and yielded the ring-opening product
in good to excellent yields.
The crystal structure of product (()-9f clearly showed that
the reaction yielded a trans ring-opening product (Figure 2).25
Figure 2. Molecular structure of (()-9f. The thermal ellipsoids
correspond to 30% probability.25
Functional groups such as alkyl, halide, alkoxy, and ester
groups were tolerated by the mild reaction conditions.
However, nitro- and cyano-substituted indoles did not react
well in this protocol. In the case of 5,6-dimethylindole, we
obtained an unseparable 70:30 mixture of two different
(
20) (a) For an overview, see: M o¨ âner, C.; Bolm, C. Catalyzed
Asymmetric Aziridinations. In Transition Metals for Organic Synthesis;
Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim, 2004; Vol. 2, pp 389-
4
2
02. (b) For a review, see: M u¨ ller, P.; Fruit, C. Chem. ReV. 2003, 103,
905-2919. (c) For recent developments with Au and Ag, see: Li, Z.;
Ding, X.; He, C. J. Org. Chem. 2006, 71, 5876-5880. Cui, Y.; He, C. J.
Am. Chem. Soc. 2003, 125, 16202-16203.
(21) Jeong, J. U.; Tao, B.; Sagasser, I.; Henniges, H.; Sharpless, K. B.
J. Am. Chem. Soc. 1998, 120, 6844-6845.
(22) Stewart, I. C.; Lee, C. C.; Bergmann, R. G.; Toste, F. D. J. Am.
Chem. Soc. 2005, 127, 17616-17617.
(
23) Nadir, U. K.; Singh, A. Tetrahedron Lett. 2005, 46, 2083-2086.
(24) (a) Hudlicky, T.; Rinner, U.; Finn, K. J.; Ghiviriga, I. J. Org. Chem.
2
005, 70, 3490-3499. (b) Minakata, S.; Hotta, T.; Oderaotoshi, Y.;
Komatsu, M. J. Org. Chem. 2006, 71, 7471-7472.
25) X-ray crystallographic study of 9f: data were collected with a
(
STOE-IPDS diffractometer using graphite-monochromated Mo KR radiation.
The structure was solved by direct methods [SIR2004: Burla, M. C.;
Caliandro, R.; Camalli, M.; Carrozzini, B.; Cascarano, G. L.; De Caro, L.;
a
Reaction conditions: aziridine (()-8 (113 mg, 0.20 mmol), indole
derivative (2.00 mmol), activated silica (0.040-0.063 mm, 429 mg), 70
C, Ar, overnight. Isolated yield.
b
°
Giacovazzo, C.; Polidori, G.; Spagna, R. J. Appl. Cryst. 2005, 38, 381-
2
3
89] and refined by full-matrix least-squares techniques against F [Sheld-
rick, G. M. SHELXL-97; University of G o¨ ttingen: Germany, 1997.] XP
BRUKER AXS) was used for a structural representation. Space group
P21/c, monoclinic, a ) 13.641(3), b ) 16.424(3), c ) 12.005(2) Å, b )
employing an understoichiometric amount of chloramine-T
trihydrate (1 equiv) in the presence of only 5 mol % of
phenyltrimethylammonium tribromide (PTAB) and 2 equiv
of 7 to reduce side products such as the brominated olefin
(
3
-3
9
4.29(3)°, V ) 2682.1(9) Å , Z ) 4, rcalcd ) 1.354 g/cm , 28 216 reflections
measured, 4732 were independent of symmetry, of which 2669 were
2
observed (I > 2s(I)), R1 ) 0.042, wR (all data) ) 0.090, 367 parameters.
Org. Lett., Vol. 8, No. 25, 2006
5763

For direct comparison in biological screenings, we also
prepared the analogues (()-10a-e without the tosylamide
side chain. Under similar reaction conditions, the hydroxyl
compound (()-6 yielded the corresponding bisindoles (()-
Table 2. Formation of Bisindoles (()-10a-e from (()-6a
1
0a-e in moderate to good yields (Table 2). Presumably, a
carbocation is formed in situ at the benzylic position, which
reacted afterwards in an electrophilic aromatic substitution
pathway with the various indoles. Also a reaction following
9a
Horne’s azafulvenium ion pathway seems possible. To the
best of our knowledge, this is the first direct benzylation of
indoles at the 3-position with a hydroxyl precursor under
2
6
solvent-free reaction conditions.
In summary, we have developed new synthetic protocols
for the preparation of unsymmetrical bisindoles. The ring-
opening arylation of the aziridine or the direct arylation of
the hydroxyl precursor proceeds highly regio- and stereo-
selectively with various indoles solvent free on solid support.
This reaction enables an easily manageable and fast diver-
sification pathway for a number of unsymmetrical bisindoles
and pharmaceutically interesting HMD derivatives.
Acknowledgment. The authors thank the Federal Min-
istry of Education and Research (BMBF) and the German
Research Foundation (DFG) for financial support of this
work. Dr. C. Fischer, Mrs. C. Mewes, Mrs. A. Lehmann,
Mrs. S. Buchholz (all Leibniz-Institut f u¨ r Katalyse e.V.), Dr.
D. G o¨ rdes, and Mr. E. Schmidt (all CELISCA) are acknowl-
edged for their technical and analytical support.
a
Reaction conditions: alcohol (()-6 (100 mg, 0.462 mmol), indole
derivative (4.62 mmol), activated silica (0.040-0.063 mm, 800 mg), 70
C, overnight. Isolated yield.
b
°
Supporting Information Available: Experimental pro-
cedures, characterization of all compounds, and crystal-
lographic data of (()-9f. This material is available free of
charge via the Internet at http://pubs.acs.org.
regioisomers likely caused by the electron-rich aromatic
system of the substrate.
In all cases, the functionalization took place in the
3-position of the employed indoles, which is in agreement
with an electrophilic aromatic substitution mechanism.
Interestingly, both nitrogen atoms were deprotected in situ
giving products (()-9a-n directly. This desired parallel
reaction avoids any other further deprotection steps.
OL062338P
(26) For a similar reaction employing R-amino sulfones, see: Ballini,
R.; Palmieri, A.; Petrini, M.; Torregiani, E. Org. Lett. 2006, 8, 4093-4096.
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Org. Lett., Vol. 8, No. 25, 2006