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

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. To date, over 200 bisACHTUNGTRENNUNGindole alkaloids have been isolated from various natural sources (Figure 1). Furthermore, considerable attention is 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. Herein, we report a new synthetic strategy towards bisACHTUNGTRENNUNGindoles 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. In particular, DA cyclopropanes with aryl and heteroaryl substituents are widely used for the synthesis and modification of various indole-containing molecules. 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. As part of our investigation into DA cyclopropane dimerization, 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 pentalenoACHTUNGTRENNUNG[1,6a–b]indole scaffold. Reagent cyclopropanes 1 are readily available from the corresponding indole-3-carbaldehydes through a standard synthetic sequence of Knoevenagel/Corey–Chaykovsky reactions. 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-BenACHTUNGTRENNUNGzylindoles 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, 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 [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 E-mail : [email protected] [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. Figure 1. Examples of biologically active bisindole alkaloids.