Cyclization strategies for the synthesis of macrocyclic bisindolylmaleimides

Three new approaches to the synthesis of macrocyclic bisindolylmaleimides 1 -4 have been identified. Two strategies afford 8, the penultimate intermedi ate for the synthesis of 1-4, in 73% and 32% yield by intramolecular cycliz ation of 31 and 40, respectively. The optimum synthesis of 1 was achieved i n nine steps and 15% yield by intramolecular formation of the macrocycle an d maleimide in one step by reaction of the sodium indolate of 12 with methy l indole-3-glyoxylate 47. The mechanism of this reaction has been elucidate d, using the trityl-protected derivative, to involve initial formation of t he tricarbonyl im ide 48, followed by irreversible alkylation of the indole nitrogen to generate the 17-membered macrocycle 49. Cyclization of 49 to h ydroxymaleimide 50 and subsequent dehydration afforded 8a. This approach el iminated the problem of dimerization observed in the intramolecular cycliza tion reactions.