Synthesis, crystal structure, DFT studies and biological evaluation of N-benzamido derivatives of oxahexacycloundecyl amines: A case of enantiomerism leading to molecular disorder

Abstract

To explore the reactivity of the amine in oxahexacycloundecylamines and its effect on biological properties, two di-substituted N-benzamido-oxahexacycloundecylamine derivatives were synthesized. These compounds exhibited favourable biological properties in cytotoxicity, neuroprotection and calcium influx experiments. Steric and conformational factors are proposed to play an important role in the biological activities observed and X-ray crystallographic experiments were conducted in an attempt to gain insight into the structural features of these compounds. The propyl derivative, 3-(N-(8,11-oxahexacyclo[5.4.0.02,6.03,10.05,9]-undecyl)benzamido)propyl benzoate, crystallizes in the monoclinic space group P21/c with unit cell parameters: a = 6.2838(11) Å; b = 27.833(5) Å; c = 12.630(2) Å; β = 95.457(3) Å; V = 2199.0(7) Å3; Z = 4. The crystal structure revealed the existence of enantiomerism in the oxa-bridged polycycloundecylamine residue as a result of the nitrogen attached on either side of the oxa-bridge. This enantiomerism leads to molecular disorder of this residue in the crystal over two positions with refined site-occupancy factors (s.o.f.s) of x (= 0.774(2)) and 1-x (= 0.226(2)) corresponding to the respective enantiomeric residues with S- and R-configurations at partial atoms C18A and C18B in one molecule. For each two-fold disordered chiral atom, the presence of a centre of symmetry in the crystal generates the complementary pair of partial atoms within the crystal (s.o.f.s x and 1-x), thus rendering it racemic. DFT optimization studies on the two individual enantiomers corresponding to the two residues with S- and R-configurations at C18 within the disordered structure showed almost identical geometric parameters, indicating that the disorder observed is linked to the crystal packing. The ethyl derivative also showed similar geometric parameters to its propyl counterpart according to the DFT results. These findings correspond to earlier observations in that a number of steric and electronic factors could collectively be responsible for the biological activities observed for these compounds.