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DOI : 10.1002/chem.201101687

Domino Cyclodimerization of Indole-Derived DonorAcceptor Cyclopropanes: One-Step Construction of the PentalenoACHTUNGRE[1,6-a,b]indole Skeleton
Olga A. Ivanova,[a] Ekaterina M. Budynina,[a, b] Alexey O. Chagarovskiy,[a, Eduard R. Rakhmankulov,[a] Igor V. Trushkov,[a, b] Alexander V. Semeykin, Nikolay L. Shimanovskii,[c] and Mikhail Ya. Melnikov*[a]
b] [c]

Bisindoles represent an extensive group of both naturally occurring and synthetically available compounds with a broad range of biological activities, such as antitumor, antiviral, and antibacterial activities.[1] To date, over 200 bisACHTUNGREindole alkaloids have been isolated from various natural sources[2] (Figure 1). Furthermore, considerable attention is

Figure 1. Examples of biologically active bisindole alkaloids.

[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 13, Moscow 119991 (Russia) Fax : (+ 7) 495-9391814 E-mail : melnikov@excite.chem.msu.ru [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.

currently being paid to the development of synthetic routes to bisindoles. Structurally, bisindoles vary significantly, resulting 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 bisACHTUNGREindoles through an interaction of two indole-derived donor acceptor (DA) cyclopropane molecules. DA cyclopropanes are of particular interest because they are promising synthetic 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.[57] In this study, we investigate in detail the dimerization of indole-containing DA cyclopropanes and present evidence for a new type of reactivity of DA cyclopropanes, which opens up routes to a novel bisindole scaffold. Coupling of DA cyclopropanes has received very little attention in the literature, with only one report thus far, which deals with the transformation of aryl 2-(3-indolyl)cyclopropyl ketones into cyclopentacarbazoles.[8] As part of our investigation into DA cyclopropane dimerization,[9] we studied the Lewis acid induced transformation of 2-(3-indolyl)cyclopropane-1,1-dicarboxylates (1). We found that this reaction yields angularly fused tetracyclic compounds 2, containing the previously unknown pentalenoACHTUNGRE[1,6ab]indole scaffold. Reagent cyclopropanes 1 are readily available from the corresponding indole-3-carbaldehydes through a standard synthetic sequence of Knoevenagel/CoreyChaykovsky reactions.[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-BenACHTUNGREzylindoles 1 were found to be more stable during storage than their N-methyl analogues. 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

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Table 1. Optimization of reaction conditions for the cyclodimerization reaction of 1a.

Entry 1 2 3 4 5 6 7

SnCl4 ACHTUNGRE[mol %] 50 120 120 190 120 120

Solvent CH3 CH3 CH3 CH3 CH3 CH2 C6H NO NO NO NO NO Cl2
6 2 2 2 2 2

Conditions T [8C] 101 20 20 60 70 42 80

t [h] 12 4 4 2 3 3 1

Yield [%][a] 6 2 5 2
[b] [c] [c]

With the optimized conditions in hand, we investigated the scope of this new domino reaction by using a series of cyclopropanes 1bi (Table 2). Cyclopropanes 1ag are readily transformed into the corresponding dimers 2ag as single diastereomers in good yields (Table 2, entries 17). Thus, this dimerization was found to be a

Figure 2. Representative NOE spectrum enhancements for 2a.

7 1 5 5

Table 2. Cyclodimerization of cyclopropanes 1 to form tetracyclic compounds 2 (Bn = benzyl, Ts = tosyl).

[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 typical for the Lewis acid induced transformation of cyclopropane-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 60 8C in the presence of 120 mol % of SnCl4 (Table 1, entry 4). Under these conditions 2a was formed as a single low-molecular weight product 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 diminished yields of 2a (Table 1, entries 57). 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. Several criteria were used to elucidate the structure of 2a : 1) the presence of double the number of resonances in the 13 C NMR spectrum points to 2a being a dimer of 1a ; 2) the presence of two ABX systems for the protons of two isolated CHюCH2 fragments in the 1H NMR specrum, which, according to the HMBC spectrum, are connected to the different CACHTUNGRE(CO2Me)2 groups ; 3) the main characteristics of an indoline system are two signals at dC = 66 and 77 ppm, which were assigned, respectively, to the quaternary C10 b and tertiary C5 a 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 corresponding to a disubstituted benzene ring. The relative stereochemistry of 2a was deduced from its NOESY spectrum. The central pentalenoACHTUNGRE[1,6ab]indole core has the only possible relative configuration, whereas the indolyl substituent at the C1 atom is arranged in a trans position relative to the indoline core (Figure 2).[13]

Entry 1 2 3 4 5 6 7 8 9

Reagent 1a 1b 1c 1d 1e 1f 1g 1h 1i

R Bn Me Bn Bn Me Bn ACHTUNGRE(CH2)3Ph Bn Ts

R' H H H H H H H Me H

X H H F Cl Br CN H H H

T [h] 2 2.5 2 2 3 2 2.5 2 2

Product 2a 2b 2c 2d 2e 2f 2g 2h 2i

Yield [%][a] 67 64 75 68 71 68 57

[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) prevented formation of the desired products (Table 2, entries 8 and 9). The structure and relative stereochemistry of dimers 2bg were established by use of spectroscopic data, which are similar to those of 2a. The structure of cyano-derivative 2f 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 zwitterionic intermediate X. In contrast, moderately activating Lewis acids in low-polar solvents usually give rise to intimate-ion-pair formation.[15, 16] The coupling of electrophilic and nucleophilic centers of two intermediates X yields dimeric 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, interaction of the malonyl anion fragment with the cationic

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Scheme 1. A possible mechanism for the formation of pentalenoACHTUNGRE[1,6ab]indoles 2.

center at C2 of the indole ring affords an angularly fused pentalenoACHTUNGRE[1,6ab]indole. 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 favorable Y-1 conformation is stabilized by orbital overlap between 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 pp* donoracceptor precomplex.[18] Electrophilic Si-face attack onto the Si face of the

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 pp* precomplex leading to close proximity of the original benzylic cation and the indole C3 atom. This transformation is a unique domino cyclodimerization reaction in which one molecule of cyclopropane reacts as a

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The PentalenoACHTUNGRE[1,6ab]indole Skeleton

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[2] [3] 2293 ; e) P. Ruiz-Sanchis, S. A. Savina, F. Alberico, M. Alvarez, Chem. Eur. J. 2011, 17, 1388 1408. M. Hesse, Alkaloids : Natures Curse or Blessing ?, Wiley, New York, 2002, p. 91. 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. Feldman, P. Ngernmeesri, Org. Lett. 2010, 12, 4502 4505 ; e) K. V. Sashidhara, 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. GarcМa-Rubia, B. Urones, R. Gomez Arrayas, J. C. Carretero, Chem. Eur. J. 2010, 16, 9676 9685 ; h) S.-Y. Chou, H. J. Tsai, Drug Dev. Res. 2011, 72, 247 258. For recent reviews on the synthesis and reactivity of DA cyclopropanes, 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. 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. For the functionalization and modification of indoles by DA cyclopropanes, 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. 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. G. Venkatesh, H. Ila, H. Junjappa, S. Mathur, V. Hush, J. Org. Chem. 2002, 67, 9477 9480. A. O. Chagarovskiy, O. A. Ivanova, E. M. Budynina, I. V. Trushkov, M. Ya. Melnikov, Tetrahedron Lett. 2011, 52, 4421 4425. 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. See the Supporting Information. For some examples, see : a) C. Kim, T. Brady, S. H. Kim, E. A. Theodorakis, 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. Our ab initio calculations at the HF/6311G level showed that 2a is 4.0 kJ molю1 more stable than its C1 epimer. See the Supporting Information. 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. P. D. Pohlhaus, S. D. Sanders, A. T. Parsons, W. Li, J. S. Johnson, J. Am. Chem. Soc. 2008, 130, 8642 8650. 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.

synthetic equivalent of 1,3-zwitterionic synthon I and the second molecule enters the reaction as a synthetic equivalent of unusual synthon II (Scheme 1). The reactivity as synthon I is typical for DA cyclopropanes,[47] whereas the reactivity as synthon II has not so far been described. We have also investigated the antitumor activity of the synthesized pentalenoACHTUNGRE[1,6ab]indoles 2. Despite low solubility, all of the compounds studied demonstrate low-to-moderate 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 pentalenoCHTUNGRE[1,6ab]indole A scaffold. During this cyclodimerization reaction, the formation of two rings, three CюC 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 participation 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 cyclopropane reactivity might also be observed for other substrates with (hetero)aromatic substituents that are prone to ipso attack. An investigation into these transformations and a further study into the physiological activities of compounds 2 are currently in progress.

[4]

[5]

[6]

Experimental Section
General procedure for synthesis of dimers 2 ag : A solution of SnCl4 (0.15 mL, 1.26 mmol) in dry nitromethane (2 mL) was added to a solution of cyclopropane 1 (1 mmol) in nitromethane (15 mL) that contained activated molecular sieves (4 ) at room temperature under an argon atmosphere. The flask containing the resulting mixture was placed in an oil bath and heated to 60 8C. The mixture was stirred for 23 h, poured into saturated aqueous NaHCO3 (15 mL), and extracted with CH2Cl2 (3 15 mL). The combined organic layers were washed with aqueous NaHCO3 (2 10 mL), water (2 10 mL), and saturated aqueous Trilon B (10 mL), dried with anhydrous Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2) afforded compounds 2.

[7]

[8] [9] [10]

Acknowledgements
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).

[11] [12]

[13]

Keywords : cyclopropanes · dimerization · domino reactions · donoracceptor systems · indoles · Lewis acids

[14]

[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. Zolfigol, H. G. Kruger, Z. Tanbakouchian, Chem. Rev. 2010, 110, 2250

[15] [16]

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Chem. 2007, 72, 7504 7510. This is in accordance with our own results for similar experiments. [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 related tetracycles : a) T. Hino, M. Nakagawa, J. Heterocycl. Chem. 1994, 31, 625 630 ; b) K. Harada, E. Kaji, K. Sasaki, S. Zen, Heterocycles 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,

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. [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

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