Synthesis of new bicyclic lactam peptidomimetics by ring-closing metathesis reactions

An efficient and versatile synthetic method for the preparation of new fused bicyclic lactams is described. The spirane cyclopentane nucleus was easily installed by diallylation of the pyroglutamate derivative followed by ring-closing metathesis (RCM). A more practical and stereoselective method for the allylation of the α-methoxy carbamate , involving the use of InCl3 as a Lewis acid, was developed. In the crucial coupling reaction of the diastereomeric mixture of cis- and trans-pirrolidine derivatives with N-Cbz vinyl phenylalanine only the cis isomer was found to react. An RCM reaction on the dipeptides followed by catalytic hydrogenation, gave the final epimeric bicyclic lactams . The same synthetic sequence on the model compound , lacking the spiro cyclopentane nucleus, is also reported.