An efficient strategy for the synthesis of asymmetrically
substituted enediynes fused to benzothiophene, benzofuran,
and indole was developed. The proposed approach is based on the
electrophilic cyclization of diacetylenes and Sonogashira coupling.
Thus, iodocyclization of readily available ortho-functionalized (buta-
1,3-diynyl)arenes was used as a direct way for the synthesis of
2-ethynyl-3-iodoheteroindenes. These substrates and their modified
derivatives were easily converted by Sonogashira coupling with acetylenes
to a variety of asymmetrically substituted acyclic enediynes
fused to heterocycles. The tolerance of the developed methodology
to a variety of functional groups is a great advantage in the synthesis
of macrocyclic enediyne systems fused to a heterocyclic core. Synthesis
of indole-fused 12-membered macrocyclic dienediyne was achieved
using ring-closing metathesis as a key step.