A full conformational characterization of 13-ethylprogestogens through theoretical calculations and nuclear magnetic resonance spectroscopy

The conformational preference of a group of 13-ethylsteoids and related estranes have been determined through theoretical calculations at B3LYp/6-31G level in order to ascertain differences and similarities in conformational behavior which might, in principle, influence the activity. Attention was focussed on two geometrical features usually related to the progestional activity of this class of compounds, namely, the inversion of the A ring and the orientation of the 13-ethyl group. The present calculations show that the absence of the C10 methyl group, like in levonorgestrel, 3-ketodesogestrel, and gestodene, makes the inversion of the A ring easier than in norethisterone andethisterone even if in any case the 1alpha,2beta-half-chair conformation remains preferred. The presence of ethyl group for the trans orientation is maintened by all the 13-ethylprogestogens though in gestodene also the g+ gauche conformation is significantly populated. This preference was experimentally supported through a high field NMR spetroscopy study of the ethylsteroids