Telescoped One-Pot Strategy for the Assembly of <i>cis</i>-4-Hydroxy-<scp>l</scp>-Prolyl Amides

In this work, a diastereoselective, straightforward, and peptide coupling reagent-free methodology for the assembly of cis-4-hydroxy-l-prolyl amides is disclosed. Following a two-step telescoped one-pot protocol, cis-4-hydroxy-l-prolyl amides are synthesized from readily available trans-4-hydroxy-l-proline. These transformations feature stereoinversion of trans-4-hydroxy-l-proline by an intramolecular Mitsunobu reaction and lactone aminolysis as a privileged approach to construct amide bonds using different amines (primary, secondary, and aromatic), amino alcohols, amino acid derivatives, and dipeptides, in high global yields (76–97%, 25 examples), without isolation of the intermediates. This methodology can be easily scalable and further upgraded into a three-step, one-pot synthesis by including an additional O-silylation step, denoting a superior performance compared to disconnected approaches, offering higher atom economy and reduced waste production. The synthetic utility of this methodology is showcased by the formal synthesis of a bioactive compound with antiamnesic properties.