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Cyclization Strategies for the Synthesis of Macrocyclic Bisindolylmaleimides

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journal contribution
posted on 16.03.2001, 00:00 by Margaret M. Faul, Christine A. Krumrich
Three new approaches to the synthesis of macrocyclic bisindolylmaleimides 14 have been identified. Two strategies afford 8, the penultimate intermediate for the synthesis of 14, in 73% and 32% yield by intramolecular cyclization of 31 and 40, respectively. The optimum synthesis of 1 was achieved in nine steps and 15% yield by intramolecular formation of the macrocycle and maleimide in one step by reaction of the sodium indolate of 12 with methyl indole-3-glyoxylate 47. The mechanism of this reaction has been elucidated, using the trityl-protected derivative, to involve initial formation of the tricarbonyl imide 48, followed by irreversible alkylation of the indole nitrogen to generate the 17-membered macrocycle 49. Cyclization of 49 to hydroxymaleimide 50 and subsequent dehydration afforded 8a. This approach eliminated the problem of dimerization observed in the intramolecular cyclization reactions.