Stereo‐ and Chemoselective Enrichment of sp3 Character in Post‐Ugi Morpholines

We conducted a systematic study on synthesis and modification of morpholine core using Ugi adducts derived from propiolic acid and glycolaldehyde dimer. The assembly step involved triphenylphosphine‐promoted 6‐exo‐dig umpolung oxa‐Michael cyclization of Ugi‐derived hydroxypropargylamides yielding 2‐methylenemorpholin‐3‐one derivatives. Subsequent heterogeneous catalytic hydrogenation of the exocyclic double bond proceeded in a highly diastereoselective fashion establishing a relative cis configuration in the resulting sp3‐enriched morpholinone scaffold. Finally, chemoselective amide reduction with lithium aluminum hydride (LAH) allowed to obtain fully saturated morpholines while leaving the more sterically hindered exocyclic amide moiety intact. Taken together these findings outline the strategy for controlled reduction of the inherent rigidity of post‐Ugi scaffolds. A comprehensive study aimed at reducing the degree of unsaturation and consequently increasing the sp3 character in post‐Ugi morpholines is conducted. The scaffold assembly involves triphenylphosphine‐promoted umpolung oxa‐Michael cyclization of Ugi adducts derived from propiolic acid and glycolaldehyde dimer. Diastereoselective heterogeneous catalytic hydrogenation, combined with chemoselective amide reduction, enables the controlled modulation of the morpholine core‘s rigidity.