Unlocking Enol-Ugi-Derived Conformationally Restricted Peptidomimetic Motifs

The enol-Ugi condensation, a versatile multicomponent reaction, provides a rapid and efficient route to enamine peptidomimetics. In this study, we investigated the factors influencing the conformational behavior of three enol-Ugi adducts with distinct structural features. Through DFT calculations and NCI analysis, we identified that noncovalent interactions, including hydrogen bonds and π-π interactions, play a pivotal role in restricting conformational flexibility. While six-membered cyclic enamines <b>6</b> and <b>7</b> exhibited varying degrees of rotational freedom, the indanone-derived enamine <b>8</b> displayed a locked conformation resembling a retropeptidic turn. These findings highlight the potential of tailoring enol-Ugi adducts to mimic biologically relevant peptidic motifs, opening new avenues for drug discovery and design.