Ab initio study of conformational stability in previtamin D, vitamin D and related model compounds

Ab initio (Hartree-Fock and density functional) calculations have been performed for previtamin D (1) and vitamin D (2) molecules with the side-chain substituted by a methyl group, and compared with the results for their simple model compounds (3-6). Both theories produce very similar optimized geometries, but differ in their estimation of the relative energies of the conformers. The density functional (B3LYP/6-31G(d)) calculations favors the axial conformations of the A-ring in 1a and 2a, whereas HF/6-31G studies lead to 50:50 axial-equatorial equilibrium. In model compounds 3-6, B3LYP/6-311-G(d,p) calculations resulted in preference of equatorial OH-orientation, while higher level (MP4(SDQ)) leads to the opposite result. The axial-equatorial equilibria in the larger biomolecules have been discussed in terms of the additional intramolecular CH/pi and OH/pi interactions caused by the presence of the CD-ring system. These results clearly demonstrate the necessity of considering the whole molecular structure surrounding the pi-system when modeling such flexible compounds, as well as the orientations of polar groups which can significantly contribute to the stability. (C) 2000 Elsevier Science B.V. All rights reserved.