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 intermediate for the synthesis of 1-4, 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.
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Lilly Research Laboratories, A Division of Eli Lilly and Company, Chemical Process Research and Development Division, Indianapolis, Indiana 46285-4813, USA.
Krumrich
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D003930:Diabetic Retinopathy / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D008301:Maleimides / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D015394:Molecular Structure; D013057:Spectrum Analysis
D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; C088060:bisindolylmaleimide