Asymmetric Modular Synthesis of a Semirigid Dipeptide Mimetic by Cascade Cycloaddition/Ring Rearrangement and Borohydride Reduction

A new
semirigid dipeptide mimetic was prepared on multigram scale,
in good yield, and in a stereocontrolled way, starting from commercially
available and unexpensive reagents, i.e., N-benzylpiperidone,
tosyl azide, and proline methyl ester. The optimized multicomponent
process consisted of a cascade click cycloaddition and a ring rearrangement
reaction, followed by a reductive step. Theoretical calculations were
performed to elucidate the reaction mechanism and support the stereochemical
outcome of the reduction. Finally, the new scaffold was used for the
preparation of model peptidomimetics, whose β turn conformation
was confirmed by dynamic NMR experiments.