Details

Autor(en) / Beteiligte

• Faul, Margaret M
• Winneroski, Leonard L
• Krumrich, Christine A
• Sullivan, Kevin A
• Gillig, James R
• Neel, David A
• Rito, Christopher J
• Jirousek, Michael R

Titel

Macrocyclic Bisindolylmaleimides:  Synthesis by Inter- and Intramolecular Alkylation

Ist Teil von

• Journal of organic chemistry, 1998-03, Vol.63 (6), p.1961-1973

Ort / Verlag

American Chemical Society

Erscheinungsjahr

1998

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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%.