Investigation of the barrier to the rotation of carbamate and amide C–N bonds in antidepressant (6aR∗,11bS∗)-7-[carbobenzyloxy-l-alanyl]-2-[(4-methylphenyl)sulfonyl]-1,2,3,4,6,6a,7,11b,2,12a(S)-decahydropyrazino[2′,1′:6,1]pyrido[3,4-b]indole by dynamic NM

Two concurrent exchanges arising due to the restricted rotation around the carbamate C–N bond and amide C–N bond were observed in (6aR∗,11bS∗)-7-[carbobenzyloxy-l-alanyl]-2-[(4-methylphenyl)sulfonyl]-1,2,3,4,6,6a,7,11b,2,12a(S)-decahydropyrazino[2′,1′:6,1]pyrido[3,4-b]indole by NMR spectroscopic experiments. A total of four low energy conformers were evaluated in the molecule, out of those, two were observed because of the restricted rotation of the amide C–N bond in CDCl3 and two were observed due to restricted carbamate C–N bond rotation in DMSO-d6 and (CD3)2CO. The barrier to the rotation (ΔG‡) around carbamate C–N bond and amide C–N bond was determined using dynamic NMR calculations. Molecular mechanics calculations also provided evidence for the presence of four low energy conformers for the compound due to restricted amide rotation and carbamate C–N bond rotation, with the value of barriers (ΔG‡) between them of the order of 15.0 kcal/mol, which is in agreement with the dynamic NMR results. Since the molecule has shown potent antidepressant activity, it is proposed that these dynamic properties could influence the activity profile of these classes of molecules.