Conformational studies of diosgenyl 2-amino-2-deoxy-β-d-glucopyranosides at the PM3 and DFT levels of theory

Abstract

Geometry optimizations at the PM3 level were performed for diosgenyl 2-amino-2-deoxy-β-d-glucopyranoside and its N-protonated form. Next, B3LYP/6-311++G∗∗ level geometry optimizations were carried out, albeit on a simpler model. The relative Gibbs free energies and geometry parameters are presented for the optimized structures. Conformational analysis concerning the clockwise (cw) and counterclockwise (ccw) arrangements of the OH groups as well as the three orientations of the NH2 and CH2OH groups was performed. Furthermore, a full scan of all the possible locations of the diosgenyl moiety in relation to the sugar ring in the target compounds was done. The PM3 optimization results indicate that diosgenyl 2-amino-2-deoxy-β-d-glucopyranoside exists as a mixture of many rotamers. Of these, ccw conformers as well as the −ac orientation of the aglycone (ca −100° for torsion angle ϕ) are preferred. In the case of the N-protonated glucoside one rotamer is dominant in the mixture (population>60%). Only the cw arrangement is stable in the protonated form, because of steric and electronic repulsion between the charged ammonium group and the hydrogen atom of the neighbouring 3-OH group. The gauche-trans (gt) orientation of the CH2OH group is favourable to both neutral and protonated forms of diosgenyl glucosides at the PM3 level. DFT studies also predict conformational mixtures for both neutral and protonated forms of simplified diosgenyl 2-amino-2-deoxy-β-d-glucopyranosides. These investigations showed unequivocally the preference for the ccw arrangement over cw, and that values of angle ϕ concur with the exo-anomeric effect. The B3LYP functional predicts the greater stability of the gt and tg orientations for the neutral and protonated analogues respectively. According to both PM3 and B3LYP calculations, torsion angle ψ has only a minor influence on the conformational energy. The importance of the geometry parameters affecting the stability of these conformers appears to be as follows: angle ϕ≈NH2/ccw/cw>gg/gt/tg>angle ψ.