Small ring constrained peptidomimetics. Synthesis of epoxy peptidomimetics, inhibitors of cysteine proteases

Different dipeptide analogues containing an oxirane ring in the place of th e peptidic bond were prepared starting from naturally occurring amino acids . N-Fmoc-amino aldehydes were transformed into the corresponding methoxyvin yl derivatives through a Wittig reaction, and the addition of PhSeCl gave a series of different alpha -phenylselenyl aldehydes. Mukajiama reaction wit h silylketene acetals gave an intermediate product that was finally transfo rmed into the desired oxiranyl peptidomimetics. Following this strategy we were able to control three new contiguous stereocenters starting from the e nantiomerically pure amino acid. The dipeptide analogues could be used in S PPS on a SASRIN resin as the final epoxides were relatively unstable under acidic conditions. Moreover the synthesis of the single dipeptide mimetics was carried out on solid phase to generate a small library of epoxy peptido mimetics. Some of the products prepared in this work resulted as time-depen dent reversible inhibitors of cysteine protease.