Synthetic Applications of Cyanoacetylated Bisindoles: Synthesis of Novel Cycloheptadiindoles, Indolocarbazoles, and Related Aza Analogues Niklas Wahlstro ¨m, ² Johnny Sla ¨tt, ² Birgitta Stensland, ‡ Anne Ertan, ‡ Jan Bergman,* ,² and Tomasz Janosik* ,² Unit for Organic Chemistry, Department of Biosciences and Nutrition, Karolinska Institute, NoVum Research Park, SE-141 57 Huddinge, Sweden and Early DeVelopment, AstraZeneca R&D, SE-151 85 So ¨derta ¨lje, Sweden jabe@biosci.ki.se (J.B.); toja@biosci.ki.se (T.J.) ReceiVed April 2, 2007 Cyclization reactions involving cyanoacetylated bisindoles have been studied, providing access to various novel cyclo- hepta[2,1-b:3,4-b′]diindole derivatives as well as some related fused pentacyclic systems. Treatment of 3-cyanoacetyl-2,3′- diindolylmethane with methanesulfonic acid gave 6-(cyano- methyl)indolo[3,2-b]carbazole in a good yield. Fused or open systems containing two indole units are rather well studied classes of heteroaromatics with diverse and sometimes striking biological effects. The indolocarbazoles 1 constitute an important group among these compounds, in particular the indolo[2,3-a]carbazole skeleton, which is present in numerous alkaloids, for example, tjipanazoles B (1, Figure 1) and F1 (2) from the blue-green alga Tolypothrix tjipanasen- sis. 2 The natural products 1 3 and 2 4 have also been studied as targets for total synthesis. Likewise, the related family of indolo- [3,2-b]carbazoles embodies a number of compounds with potent biological effects, for instance, 6-formylindolo[3,2-b]carbazole (3), 5 which is an extremely powerful aromatic hydrocarbon receptor (AhR) ligand. 6 On the other hand, the related fused systems featuring a central seven-membered ring are relatively rare 7 but may nevertheless also be encountered in nature as demonstrated by isolation of the natural product caulersin (4), 8 the structure of which has also been confirmed by total syntheses, 9 or iheyamine A (5), which incorporates an azepine ring between the two indole moieties. 10 The ready access of 3-cyanoacetyl-2,2′-biindolyl 11 (6) has prompted us to investigate routes to the cyclohepta[2,1-b:3,4- b′]diindole skeleton as it was anticipated that the reactivity of the vacant indole 3 position in combination with the synthetic versatility of the cyanoacetyl moiety 12 might offer an opportunity for construction of the central seven-membered ring. Indeed, heating of 6 with 4-chlorobenzaldehyde in acetic acid in the presence of sodium acetate gave a good yield of the cyclohepta- diindole 7 as a 4:1 mixture of cis and trans isomers (Scheme 1). Repeated recrystallization of this isomeric mixture from acetonitrile allowed enrichment of the cis isomers (J H-5-H-6 ) 3.2 Hz for the cis isomers; J H-5-H-6 ) 5.1 Hz for the trans isomers) to a cis/trans ratio higher than 20:1 as determined by ² Karolinska Institute. ‡ AstraZeneca R&D. (1) For reviews, see: (a) Bergman, J.; Janosik, T.; Wahlstro ¨m, N. AdV. Heterocycl. Chem. 2001, 80,1-71. (b) Kno ¨ lker, H.-J.; Reddy, K. R. Chem. ReV. 2002, 102, 4303-4427. (c) Prudhomme, M. Curr. Pharm. Des. 1997, 3, 265-290. (d) Sa ´nchez, C.; Me ´ndez, C.; Salas, J. A. Nat. Prod. Rep. 2006, 23, 1007-1045. (2) Bonjouklian, R.; Smitka, T. A.; Doolin, L. E.; Molloy, R. M.; Debono, M.; Shaffer, S. A.; Moore, R. E.; Stewart, J. B.; Patterson, G. M. L. Tetrahedron 1991, 47, 7739-7750. (3) Kuethe, J. 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Ber. 1981, 114, 2238-2244. (f) Baraznenok, I. L.; Nenajdenko, V. G.; Balenkova, E. S. Chem. Heterocycl. Compd. (Engl. Transl.) 2003, 39, 776- 779. (g) Kavitha, C.; Prasad, K. J. R. Asian J. Chem. 2004, 16, 40-48. (8) Su, J.-Y.; Zhu, Y.; Zeng, L.-M.; Xu, X.-H. J. Nat. Prod. 1997, 60, 1043-1044. (9) (a) Wahlstro ¨m, N.; Stensland, B.; Bergman, J. Tetrahedron 2004, 60, 2147-2153. (b) Fresneda, P. M.; Molina, P.; Saez, M. A. Synlett 1999, 1651-1653. (c) Miki, Y.; Aoki, Y.; Miyatake, H.; Minematsu, T.; Hibino, H. Tetrahedron Lett. 2006, 47, 5215-5218. (10) Sasaki, T.; Ohtani, I. I.; Tanaka, J.; Higa, T. Tetrahedron Lett. 1999, 40, 303-306. (11) Sla ¨tt, J.; Romero, I.; Bergman, J. Synthesis 2004, 2760-2765. (12) (a) Sla ¨tt, J.; Wahlstro ¨m, N.; Janosik, T.; Bergman, J. J. Heterocycl. Chem. 2005, 42, 141-145. (b) Johnson, A.-L.; Sla ¨tt, J.; Janosik, T.; Bergman, J. Heterocycles 2006, 68, 2165-2170. (c) Radwan, M. A. A.; El-Sherbiny, M. Bioorg. Med. Chem. 2007, 15, 1206-1211. FIGURE 1. Some examples of indolocarbazoles (1-3) and related alkaloids featuring a central seven-membered ring (4 and 5). 5886 J. Org. Chem. 2007, 72, 5886-5889 10.1021/jo0706729 CCC: $37.00 © 2007 American Chemical Society Published on Web 06/22/2007