Evaluation of alternative approaches for the synthesis of macrocyclic bisindolylmaleimides

Approaches for the synthesis of macrocyclic bisindolylmaleimides, in which the indole nitrogens are linked with a tether, are described. Two alternative approaches were investigated: macrocyclisation in either the 'southern' (by adding the tether to the bisindolylmaleimide ring system) or the 'northern' district. With two-, three- and four-atom tethers, both of these approaches were unsuccessful for a wide range of attempted macrocyclisation reactions (palladium-catalysed pi-allyl substitution, ring-closing metathesis, McMurry reaction, iodocyclisation, formation of a silylene derivative, substitution of an alpha,omega-disubstituted electrophile). The failure of all of these reactions was ascribed to the strained nature of the target ring system. However, with longer tethers (six to ten atoms), the macrocycles could prepared using either a ring-closing metathesis reaction or by substitution of an alpha,omega-dibromide). Fourteen successful macrocyclisation reactions are described; deprotection gave eleven macrocyclic bisindolylmaleimides in which an imide substituent had been removed.