Conformation of Progesterone Side Chain: Conflict between X-ray Data and Force-Field Calculations

In corticoids and progestins, the orientation of the 20-keto group relative to the bulk of the steroid influences biological activity. Crystallographic data on 85 pregnane structures having a 20-one substituent provide information on 17β-side-chain flexibility. In 81 structures the C( 16)-C( 17)-C(20)-0(20) torsion angle is between 0 and -46°. This is consistent with CD, IR, and NMR solution spectra and more precisely defines the side-chain conformation in solution. The 4 structures whose side chains lie outside this range do so because of a 16β substituent and not because of crystal packing forces. The data indicate that for 16β-substituted structures two equienergy conformers exist. This is in agreement with interpretation of CD spectra and again provides a precise characterization of the minimum energy conformation. The data show that the secondary conformation is attained by opening an sp³ 4C-C-C angle at C( 17) to 120°, relieving the steric interaction between 0(20) and C(18). The only inconsistency between solution spectra and solid-state conformation concerns the failure to observe an intramolecular hydrogen bond between 0(17a) and 0(20). The data indicate that such an intramolecular hydrogen bond will introduce considerable steric strain between the methyl groups. The failure to observe an intramolecular hydrogen bond in the four crystal structures in the sample where it might have been expected is probably due to competition for the hydrogen-bond donor from 0(3) and 0(11) acceptors. The conclusions drawn recently from force-field calculations for rotation of the 17β side group in these molecules is, however, at marked variance with the crystallographic data. Not one of the 85 structures is found to have a conformation in which the C( 16)-C( 17)-C(20)-0(20) torsion angle is within 15° of a commonly calculated minimum energy position of 60°. Neither 17α-hydroxy, 17α-methyl, nor 21-hydroxy substitution alone has a significant influence on side-chain orientation. However, 17β,21-dihydroxy substitution and 21-acetoxy or 16a substitution all shift the side chain away from the normal position by an average of-15°. The narrow range of side-chain conformations seen in very different crystalline environments in the 85 crystal structure determinations, the predictable substituent influence apparent in the data, and the bond angle deformation observed in the 16β-substituted structures strongly suggest that crystallographically observed conformers seldom deviate from minimum energy positions regardless of hypothetical broad energy minima, metastable states, and small barriers to rotation. The programs presently used for minimum energy calculations fail to represent intramolecular forces accurately.