Synthesis and Analysis of the Conformational Preferences of 5-Aminomethyloxazolidine-2,4-dione Scaffolds: First Examples of β2- and β2,2-Homo-Freidinger Lactam Analogues

Constrained peptidomimetic scaffolds are of considerable interest for the design of therapeutically useful analogues of bioactive peptides. We present the single-step cyclization of (S)- or (R)-alpha-hydroxy-I32- or alpha-substituted-alpha-hyd roxy-I32'2-amino acids already incorporated within oligopeptides to 5-aminomethyl-oxazolidine-2,4-dione (Amo) rings. These scaffolds can be regarded as unprecedented 132- or 132'2-homo-Freidinger lactam analogues, and can be equipped with a proteinogenic side chain at each residue. 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 alpha-substituents.