Telescoped\nOne-Pot Strategy for the Assembly of <i>cis</i>-4-Hydroxy‑l‑Prolyl Amides

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