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.