Macrocyclic Bisindolylmaleimides: Synthesis by Inter- and Intramolecular Alkylation

Autor:	Michael R. Jirousek, Kevin A. Sullivan, Gillig James Ronald, Leonard L. Winneroski, Christine A. Krumrich, David Andrew Neel, Margaret M. Faul, Christopher John Rito
Rok vydání:	1998
Předmět:	Bisindolylmaleimide Organic Chemistry Intermolecular force Alkylation Combinatorial chemistry law.invention chemistry.chemical_compound chemistry Active compound law Intramolecular force Yield (chemistry) Stereoselectivity Crystallization
Zdroj:	The Journal of Organic Chemistry. 63:1961-1973
ISSN:	1520-6904 0022-3263
DOI:	10.1021/jo971980h
Popis:	Macrocyclic bisindolylmaleimides 1−4 have been identified as competitive reversible inhibitors of PKC β1 and β2 and are being advanced to the clinic for evaluation as a treatment of retinopathy associated with diabetic complications. Highly convergent and stereoselective syntheses of 1−4 have been developed. The key synthetic step involves intermolecular alkylation of symmetrical bisindolylmaleimide 9 with chiral bisalkylating agent 8c and is amenable to the preparation of multikilogram quantities of these compounds. The synthetic sequence to 1, the most active compound, proceeds in 11 steps and 26% overall yield (>98% ee) from (R)-1-chloro-2,3-propanediol. No chromatographic purifications are required throughout the process and the final product is isolated in >97% purity after crystallization from DMF/MeOH. Synthesis of 1−4 by intramolecular alkylation proved less efficient, requiring 17 steps and affording 1−4 in lower overall yields of 6.0−8.5%.
Databáze:	OpenAIRE
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