Domino cyclodimerization of indole-derived donor-acceptor cyclopropanes: One-step construction of the pentaleno[1,6-a,b]indole skeleton

Article abstract of DOI:10.1002/chem.201101687

The fellowship of the rings: The previously undiscovered ability of indole-derived donor-acceptor cyclopropanes to involve four reaction centers simultaneously was revealed by their domino cyclodimerization (see scheme). This SnCl₄-induced reac

Full text of DOI:10.1002/chem.201101687

DOI: 10.1002/chem.201101687
Domino Cyclodimerization of Indole-Derived Donor–Acceptor
Cyclopropanes: One-Step Construction of the Pentaleno
Skeleton
ACHTUNGTREN[NGNU 1,6-a,b]indole
Olga A. Ivanova,[a] Ekaterina M. Budynina,[a, b] Alexey O. Chagarovskiy,[a, b]
Eduard R. Rakhmankulov,[a] Igor V. Trushkov,[a, b] Alexander V. Semeykin,[c]
Nikolay L. Shimanovskii,[c] and Mikhail Ya. Melnikov*[a]
Bisindoles represent an extensive group of both naturally
occurring and synthetically available compounds with a
broad range of biological activities, such as antitumor, anti-
viral, and antibacterial activities.[1] To date, over 200 bis-
currently being paid to the development of synthetic routes
to bisindoles. Structurally, bisindoles vary significantly, re-
sulting in a lack of general methods for the synthesis of
these compounds, although, most synthetic approaches are
based on the coupling of two indole-containing molecules.[3]
Herein, we report a new synthetic strategy towards bis-
ACHTUNGTRENNUNGindole alkaloids have been isolated from various natural
sources[2] (Figure 1). Furthermore, considerable attention is
AHCTUNGTREGiNNUN ndoles through an interaction of two indole-derived donor–
acceptor (DA) cyclopropane molecules. DA cyclopropanes
are of particular interest because they are promising syn-
thetic reagents with versatile reactivity.[4] In particular, DA
cyclopropanes with aryl and heteroaryl substituents are
widely used for the synthesis and modification of various
indole-containing molecules.[5–7] In this study, we investigate
in detail the dimerization of indole-containing DA cyclopro-
panes and present evidence for a new type of reactivity of
DA cyclopropanes, which opens up routes to a novel bisin-
dole scaffold.
Coupling of DA cyclopropanes has received very little at-
tention in the literature, with only one report thus far, which
deals with the transformation of aryl 2-(3-indolyl)cycloprop-
yl ketones into cyclopentacarbazoles.[8] As part of our inves-
tigation into DA cyclopropane dimerization,[9] we studied
the Lewis acid induced transformation of 2-(3-indolyl)cyclo-
propane-1,1-dicarboxylates (1). We found that this reaction
yields angularly fused tetracyclic compounds 2, containing
Figure 1. Examples of biologically active bisindole alkaloids.
the previously unknown pentalenoACTHUNTGRNEUNG[1,6a–b]indole scaffold.
Reagent cyclopropanes 1 are readily available from the cor-
responding indole-3-carbaldehydes through a standard syn-
thetic sequence of Knoevenagel/Corey–Chaykovsky reac-
tions.[10] These cyclopropanes have low stability at elevated
temperatures and on silica gel, but can be isolated as pure
materials by chromatography on neutral alumina. N-Ben-
[a] Dr. O. A. Ivanova, Dr. E. M. Budynina, Dr. A. O. Chagarovskiy,
E. R. Rakhmankulov, Dr. I. V. Trushkov, Prof. M. Y. Melnikov
Department of Chemistry
M. V. Lomonosov Moscow State University
Leninskie Gory 1–3, Moscow 119991 (Russia)
Fax : (+7)495-9391814
AHCTUNGTREGzNNUN ylindoles 1 were found to be more stable during storage
than their N-methyl analogues.
E-mail: melnikov@excite.chem.msu.ru
To find the optimal conditions for the Lewis acid induced
DA cyclopropane dimerization, we selected cyclopropane
1a as a model substrate. Building on a previous study of the
related indole-substituted DA cyclopropanes,[8] we started
by using the SnCl4/CH3NO2 system as the reaction initiator
(Table 1). It is noteworthy that the reaction without Lewis
acid leads to complete destruction of 1a into a mixture of
polymeric and ring-opened byproducts (Table 1, entry 1). If
[b] Dr. E. M. Budynina, Dr. A. O. Chagarovskiy, Dr. I. V. Trushkov
Laboratory of Chemical Synthesis, Federal Research Center of
Pediatric Hematology, Oncology, and Immunology
Leninskii av. 117/2, Moscow 117997 (Russia)
[c] Dr. A. V. Semeykin, Prof. N. L. Shimanovskii
Medico-Biological Faculty, The Russian State Medical University
Bolshaya Pirogovskaya st. 9A, Moscow 119435 (Russia)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101687.
11738
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 11738 – 11742

COMMUNICATION
Table 1. Optimization of reaction conditions for the cyclodimerization
reaction of 1a.
With the optimized condi-
tions in hand, we investigated
the scope of this new domino
reaction by using a series of cy-
clopropanes 1b–i (Table 2). Cy-
clopropanes 1a–g are readily
transformed into the corre-
sponding dimers 2a–g as single
diastereomers in good yields
(Table 2, entries 1–7). Thus, this
dimerization was found to be a
Figure 2. Representative NOE
spectrum enhancements for
2a.
Entry
SnCl4
[mol%]
Conditions
Yield
[%][a]
U
Solvent
T [8C]
t [h]
[b]
1
2
3
4
5
6
7
–
50
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH2Cl2
C6H6
101
20
20
60
70
42
80
12
4
4
2
3
–
–
–
[c]
Table 2. Cyclodimerization of cyclopropanes 1 to form tetracyclic com-
pounds 2 (Bn=benzyl, Ts=tosyl).
[c]
120
120
190
120
120
67
21
55
25
3
1
[a] Isolated yield. [b] Unidentified products. [c] Lactone 3 was the only
isolated product (78% yield).
the reaction was performed in the presence of SnCl4 at
room temperature, cyclopropane 1a yielded only lactone
3[11] (Table 1, entries 2 and 3). This lactone formation is typi-
cal for the Lewis acid induced transformation of cyclopro-
pane-1,1-diesters.[12] In this case, variation of the quantity of
Lewis acid had no effect on the reaction results. However,
increasing the reaction temperature led to the formation of
dimeric product 2a. The best yield of 2a was obtained if the
reaction was performed at 608C in the presence of
120 mol% of SnCl4 (Table 1, entry 4). Under these condi-
tions 2a was formed as a single low-molecular weight prod-
uct in 67% yield. Any further increase in the temperature,
variation of the Lewis acid loading or change to a low-polar
or non-polar solvent (CH2Cl2, benzene) resulted in dimin-
ished yields of 2a (Table 1, entries 5–7).
Entry
Reagent
R
R’
X
T
[h]
Product
Yield
[%][a]
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1 f
1g
1h
1i
Bn
Me
Bn
Bn
Me
Bn
H
H
H
H
H
H
H
Me
H
H
H
F
Cl
Br
CN
H
H
H
2
2.5
2
2
3
2
2.5
2
2a
2b
2c
2d
2e
2 f
2g
2h
2i
67
64
75
68
71
68
57
–
A
Bn
Ts
2
–
[a] Isolated yield.
generally applicable reaction for N-alkylindoles 1. However,
the presence of an acceptor substituent on N1 (1i) or even a
small substituent on C2 of the indole moiety in 1 (1h) pre-
vented formation of the desired products (Table 2, entries 8
and 9). The structure and relative stereochemistry of dimers
2b–g were established by use of spectroscopic data, which
are similar to those of 2a. The structure of cyano-derivative
2 f has been unambiguously proven by single-crystal X-ray
analysis.[14]
A possible mechanism for the cyclodimerization of 1 to
form 2 is shown in Scheme 1. The presence of a strong
Lewis acid in a polar solvent, such as nitromethane, induces
the cyclopropane ring-opening reaction, affording zwitter-
ionic intermediate X. In contrast, moderately activating
Lewis acids in low-polar solvents usually give rise to inti-
mate-ion-pair formation.[15,16] The coupling of electrophilic
and nucleophilic centers of two intermediates X yields di-
meric zwitterionic intermediate Y. This step is analogous to
the first step in the dimerization of 2-(indolyl)cyclopropyl
ketones.[8] However, the next step is dramatically different;
attack of the electrophilic center in Y on C3 of the indole
ring occurs to give zwitterionic intermediate Z.[17] Finally, in-
teraction of the malonyl anion fragment with the cationic
Compound 2a is formed as a single diastereomer. Its
structure was assigned by use of 1D and 2D COSY,
HETCOR, HMBC, and NOESY NMR spectral data. Sever-
al criteria were used to elucidate the structure of 2a: 1) the
presence of double the number of resonances in the
13C NMR spectrum points to 2a being a dimer of 1a; 2) the
presence of two ABX systems for the protons of two isolat-
1
À
ed CH CH2 fragments in the H NMR specrum, which, ac-
cording to the HMBC spectrum, are connected to the differ-
ent CACHTUNGTRENNUNG(CO2Me)2 groups; 3) the main characteristics of an in-
doline system are two signals at dC =66 and 77 ppm, which
were assigned, respectively, to the quaternary C10b and ter-
tiary C5a atoms; and 4) the presence in the aromatic region
of only one set of signals for 3-substituted indole, whereas
the indoline system is represented by resonances corre-
sponding to a disubstituted benzene ring. The relative ste-
reochemistry of 2a was deduced from its NOESY spectrum.
The central pentalenoACTHNUTRGNE[NUG 1,6a–b]indole core has the only possi-
ble relative configuration, whereas the indolyl substituent at
the C1 atom is arranged in a trans position relative to the in-
doline core (Figure 2).[13]
Chem. Eur. J. 2011, 17, 11738 – 11742
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11739

M. Y. Melnikov et al.
Scheme 1. A possible mechanism for the formation of pentalenoACTHNUTRGNEU[GN 1,6a–b]indoles 2.
center at C2 of the indole ring affords an angularly fused
pentaleno[1,6a–b]indole.
nucleophile followed by cyclization results in the formation
of 2. The alternative electrophilic Re-face attack onto the Si
face of the nucleophile (Y-2), leading to the C1 epimer of 2,
does not occur due to the reduced orbital overlap and
higher steric repulsion in Y-2 relative to Y-1. Remarkably,
the chemo- and regioselectivity of the formation of 2 can
also be explained by the formation of a p–p* precomplex
leading to close proximity of the original benzylic cation
and the indole C3 atom.
ACHTUNGTRENNUNG
The stereochemical outcome of this reaction is defined
during the transformation of Y into Z and can be explained
in terms of the possible conformations of zwitterion Y
before the electrophilic ipso attack (Scheme 1). The favora-
ble Y-1 conformation is stabilized by orbital overlap be-
tween the two indole moieties, one of which is electron poor
due to conjugation with the cationic center. This overlap
leads to the formation of a p–p* donor–acceptor precom-
plex.[18] Electrophilic Si-face attack onto the Si face of the
This transformation is a unique domino cyclodimerization
reaction in which one molecule of cyclopropane reacts as a
11740
www.chemeurj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 11738 – 11742

The PentalenoACHTUNGTRENNUNG[1,6a–b]indole Skeleton
COMMUNICATION
2293; e) P. Ruiz-Sanchis, S. A. Savina, F. Alberico, M. Alvarez,
Chem. Eur. J. 2011, 17, 1388–1408.
[2] M. Hesse, Alkaloids: Natureꢀs Curse or Blessing?, Wiley, New York,
2002, p. 91.
synthetic equivalent of 1,3-zwitterionic synthon I and the
second molecule enters the reaction as a synthetic equiva-
lent of unusual synthon II (Scheme 1). The reactivity as syn-
thon I is typical for DA cyclopropanes,[4–7] whereas the reac-
tivity as synthon II has not so far been described.
[3] For some recent examples, see: a) L. Fu, G. W. Gribble, Tetrahedron
Lett. 2010, 51, 537–539; b) K. Zhao, S.-L. Zhu, D.-Q. Shi, X.-P. Xu,
S.-J. Ji, Synthesis 2010, 1793–1803; c) J. Yang, Z. Wang, F. Pan, Y.
Li, W. Bao, Org. Biomol. Chem. 2010, 8, 2975–2978; d) K. S. Feld-
man, P. Ngernmeesri, Org. Lett. 2010, 12, 4502–4505; e) K. V. Sa-
shidhara, A. Kumar, M. Kumar, A. Srivastava, A. Puri, Bioorg.
Med. Chem. Lett. 2010, 20, 6504–6507; f) P. Va, E. L. Campbell,
W. M. Robertson, D. L. Boger, J. Am. Chem. Soc. 2010, 132, 8489–
8495; g) A. Garcꢃa-Rubia, B. Urones, R. Gomez Arrayas, J. C. Car-
retero, Chem. Eur. J. 2010, 16, 9676–9685; h) S.-Y. Chou, H. J. Tsai,
Drug Dev. Res. 2011, 72, 247–258.
[4] For recent reviews on the synthesis and reactivity of DA cyclopro-
panes, see: a) H.-U. Reissig, R. Zimmer, Chem. Rev. 2003, 103,
1151–1196; b) M. Yu, B. L. Pagenkopf, Tetrahedron 2005, 61, 321–
347; c) D. Agrawal, V. K. Yadav, Chem. Commun. 2008, 6471–6488;
d) F. De Simone, J. Waser, Synthesis 2009, 3353–3374; e) C. A.
Carson, M. A. Kerr, Chem. Soc. Rev. 2009, 38, 3051–3060.
[5] For the construction of indole rings by use of the reactions of DA
cyclopropanes, see: a) C. L. Morales, B. L. Pagenkopf, Org. Lett.
2008, 10, 157–159; b) M. B. Johansen, M. A. Kerr, Org. Lett. 2008,
10, 3497–3500; c) B. Bajtos, B. L. Pagenkopf, Eur. J. Org. Chem.
2009, 1072–1077; d) M. M. A. R. Moustafa, B. L. Pagenkopf, Org.
Lett. 2010, 12, 3168–3171.
[6] For the functionalization and modification of indoles by DA cyclo-
propanes, see: a) G. Venkatesh, P. P. Singh, H. Ila, H. Junjappa, Eur.
J. Org. Chem. 2006, 5378–5386; b) M. Tanaka, M. Ubukata, T.
Matsuo, K. Yasue, K. Matsumoto, Y. Kajimoto, T. Ogo, T. Inaba,
Org. Lett. 2007, 9, 3331–3334; c) B. Bajtos, M. Yu, H. Zhao, B. L.
Pagenkopf, J. Am. Chem. Soc. 2007, 129, 9631–9634; d) B. Bajtos,
B. L. Pagenkopf, Org. Lett. 2009, 11, 2780–2783; e) A. Karadeolian,
M. A. Kerr, Angew. Chem. 2010, 122, 1151–1153; Angew. Chem.
Int. Ed. 2010, 49, 1133–1135; f) A. Karadeolian, M. A. Kerr, J. Org.
Chem. 2010, 75, 6830–6841; g) H. K. Grover, T. P. Lebold, M. A.
Kerr, Org. Lett. 2011, 13, 220–223.
[7] For the transformations of DA cyclopropanes containing an indole
ring, see: a) A. K. Yadav, S. Peruncheralathan, H. Ila, H. Junjappa,
J. Org. Chem. 2007, 72, 1388–1394; b) K. Sapeta, M. A. Kerr, Org.
Lett. 2009, 11, 2081–2084; c) F. De Simone, J. Gertsch, J. Waser,
Angew. Chem. 2010, 122, 5903–5906; Angew. Chem. Int. Ed. 2010,
49, 5767–5770.
We have also investigated the antitumor activity of the
synthesized pentalenoACTHNUTRGNE[NUG 1,6a–b]indoles 2. Despite low solubili-
ty, all of the compounds studied demonstrate low-to-moder-
ate cytotoxicity towards HeLa cancer cells.[11]
In conclusion, we have discovered a domino reaction of
readily available 2-(3-indolyl)cyclopropane-1,1-diesters that
produces cyclic dimers with the pentalenoACTHUNRTGNEUNG[1,6a–b]indole
scaffold. During this cyclodimerization reaction, the forma-
À
tion of two rings, three C C s bonds and four stereogenic
centers occurs with exceptionally high chemo-, regio-, and
stereoselectivity. In this reaction the DA cyclopropanes
demonstrate a conceptually new type of reactivity with par-
ticipation of four reaction sites: two nucleophilic (the C1
atom of the cyclopropane ring and the C2 atom of indole)
and two electrophilic (the C3 atom of the cyclopropane ring
and the C2 atom of indole) centers. This new kind of DA cy-
clopropane reactivity might also be observed for other sub-
strates with (hetero)aromatic substituents that are prone to
ipso attack. An investigation into these transformations and
a further study into the physiological activities of com-
pounds 2 are currently in progress.
Experimental Section
General procedure for synthesis of dimers 2a–g: A solution of SnCl4
(0.15 mL, 1.26 mmol) in dry nitromethane (2 mL) was added to a solu-
tion of cyclopropane 1 (1 mmol) in nitromethane (15 mL) that contained
activated molecular sieves (4 ꢁ) at room temperature under an argon at-
mosphere. The flask containing the resulting mixture was placed in an oil
bath and heated to 608C. The mixture was stirred for 2–3 h, poured into
saturated aqueous NaHCO3 (15 mL), and extracted with CH2Cl2 (3ꢂ
15 mL). The combined organic layers were washed with aqueous
NaHCO3 (2ꢂ10 mL), water (2ꢂ10 mL), and saturated aqueous Trilon B
(10 mL), dried with anhydrous Na2SO4, and concentrated under reduced
pressure. Purification by column chromatography (SiO2) afforded com-
pounds 2.
[8] G. Venkatesh, H. Ila, H. Junjappa, S. Mathur, V. Hush, J. Org.
Chem. 2002, 67, 9477–9480.
[9] A. O. Chagarovskiy, O. A. Ivanova, E. M. Budynina, I. V. Trushkov,
M. Ya. Melnikov, Tetrahedron Lett. 2011, 52, 4421–4425.
[10] a) E. J. Corey, M. Chaykovsky, J. Am. Chem. Soc. 1965, 87, 1353–
1364; b) W. Fraser, C. J. Suckling, H. C. S. Wood, J. Chem. Soc.
Perkin Trans. 1 1990, 3137–3144.
[11] See the Supporting Information.
Acknowledgements
[12] For some examples, see: a) C. Kim, T. Brady, S. H. Kim, E. A. Theo-
dorakis, Synth. Commun. 2004, 34, 1951–1965; b) S. D. R. Christie,
R. J. Davoile, R. C. F. Jones, Org. Biomol. Chem. 2006, 4, 2683–
2684; c) G. Yang, Y. Shen, K. Li, Y. Sun, Y. Hua, J. Org. Chem.
2011, 76, 229–233.
We thank Prof. K. A. Lyssenko (INEOS RAS) for the X-ray analysis.
This work was supported by the Russian Foundation of Basic Research
(Project 09-03-00244-a).
[13] Our ab initio calculations at the HF/6–311G level showed that 2a is
4.0 kJmolÀ1 more stable than its C1 epimer. See the Supporting In-
formation.
[14] CCDC-819454 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
[15] P. D. Pohlhaus, S. D. Sanders, A. T. Parsons, W. Li, J. S. Johnson, J.
Am. Chem. Soc. 2008, 130, 8642–8650.
[16] For the irreversibility of DA cyclopropane ring-opening reactions in
the presence of strong Lewis acids, see, for example: V. S. Korotkov,
O. V. Larionov, A. Hofmeister, J. Magull, A. de Meijere, J. Org.
Keywords: cyclopropanes
reactions · donor–acceptor systems · indoles · Lewis acids
·
dimerization
·
domino
[1] a) R. J. Sundberg, S. Q. Smith in The Alkaloids, Vol. 59 (Ed.: G. A.
Cordell), Academic Press, Amsterdam, 2002, pp. 281–376; b) T.-S.
Kam, Y.-M. Choo in The Alkaloids, Vol. 63 (Ed.: G. A. Cordell),
Academic Press, Amsterdam, 2006, pp. 181–337; c) K. S. Ryan, C. L.
Drennan, Chem. Biol. 2009, 16, 351–364; d) M. Shiri, M. A. Zolfi-
gol, H. G. Kruger, Z. Tanbakouchian, Chem. Rev. 2010, 110, 2250–
Chem. Eur. J. 2011, 17, 11738 – 11742
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11741

M. Y. Melnikov et al.
Chem. 2007, 72, 7504–7510. This is in accordance with our own re-
sults for similar experiments.
A. Bertamino, C. Aquino, O. Mazzoni, M. V. Diurno, R. Iacovino,
M. Saviano, M. Sala, E. Novellino, P. Grieco, Eur. J. Org. Chem.
2008, 1983–1992.
[17] This preference for ipso alkylation of the C3 atom in 3-alkylindoles
over electrophilic attack onto the C2 position has been documented
in many cases. In particular, it has been used for the synthesis of re-
lated tetracycles: a) T. Hino, M. Nakagawa, J. Heterocycl. Chem.
1994, 31, 625–630; b) K. Harada, E. Kaji, K. Sasaki, S. Zen, Hetero-
cycles 1996, 42, 289–304; c) R. Hili, A. K. Yudin, J. Am. Chem. Soc.
2006, 128, 14772–14773; d) I. M. Gomez-Monterrey, P. Campiglia,
[18] O. A. Ivanova, E. M. Budynina, A. O. Chagarovskiy, A. E. Kaplun,
I. V. Trushkov, M. Ya. Melnikov, Adv. Synth. Catal. 2011, 353, 1125–
1134.
Received: June 2, 2011
Published online: September 12, 2011
11742
www.chemeurj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 11738 – 11742