Stereoselective Synthesis of cis,cis‐Configured Vicinal Triamines

The first stereoselective synthesis of a cis,cis-configured vicinal triamine was achieved, starting from N-cyclohexenylpyrrolidone (10). The reaction sequence consists of the stereoselective construction of the trans-configured 1,3-diamide 14, trans-to-cis isomerization via enols or enamines, and subsequent highly stereoselective reduction of the intermediate imine 17D to the amine 18A. The postulated reaction pathway explains the observed stereoconvergence and is supported by calculation of the heats of formation of its intermediates at the PM3 level. LiAlH4 reduction of 18A yielded the tetracyclic aminal 19, which was converted into the pyrrolidinylquinoxaline 7, which showed low to moderate affinity towards κ and σ1 receptors.