Synthesis of beta2- and beta2,2-homo-Freidinger Lactam analogs, conformational analysis, and applications in Medicinal Chemistry

The cyclization of isoSer incorporated into short peptides with DSC and DIPEA was performed either in solution or in solid phase with very good yields, and allowed preparing in a single step peptidomimetics containing the fivemembered Amo ring comprising isoSer and the following residue. This unusual scaffold represents a unprecedented beta2-homo variant of the classic Freidinger lactams. Besides, the availability of optically pure alfa-substituted alfa-hydroxy- beta2,2-amino acid residues allowed preparing peptidomimetics carrying substituents at all alfa-positions. In a biomimetic environment, Amo rings act as inducers of extended, semi-bent or folded geometries, depending on the relative stereochemistry and the presence of the alfa-substituent. Conformational analysis indicated that the constrained alfa-substituted Amo tends to favour in homochiral oligomers a rare pseudo beta-turn stabilized by a 9- membered hydrogen bond in the opposite direction of the sequence. Studies are currently in progress in our group for the preparation and analysis of the conformational preference of oligopeptides composed of repetitive Amo units, alone or in combination with other residues. For the simple synthetic protocol and the atypical geometric features, the Amo scaffold deserves to be exploited for the design of new conformationally biased peptidomimetics or foldamers. In this respect, herein we anticipate unprecedented mimetics of the potent opioid peptide endomorphin-1 and of the peptidomimetic BIO1211, a selective ligand of alfa4beta1-integrins.