MACROCYCLIC BISINDOLYLMALEIMIDES - SYNTHESIS BY INTERMOLECULAR AND INTRAMOLECULAR ALKYLATION

Macrocyclic bisindolylmaleimides 1-4 have been identified as competiti ve reversible inhibitors of PKC beta(1) and beta(2) and are being adva nced to the clinic for evaluation as a treatment of retinopathy associ ated with diabetic complications. Highly convergent and stereoselectiv e syntheses of 1-4 have been developed. The key synthetic step involve s intermolecular alkylation of symmetrical bisindolylmaleimide 9 with chiral bisalkylating agent 8c and is amenable to the preparation of mu ltikilogram 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 purif ications 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 1? steps and affording 1-4 in lower overall yields of 6.0-8.5%.