Synthesis of cleavamine-type indole alkaloids and their 5-nor derivatives by a ring-closing metathesis–vinyl halide Heck cyclization strategy

An indole-templated RCM has been used to assemble the central medium-sized rings of the indole upper-half of vinorelbine and the cleavamine-type alkaloids. From these key intermediates, the bridged tetracyclic framework of the alkaloids is completed with the insertion of a 2-ethylpropeno unit, by N-alkylation followed by a challenging endocyclic vinyl halide Heck cyclization. The usefulness of the approach is illustrated with the synthesis of (±)-cleavamine and (±)-dihydrocleavamine.