Conformational equilibria in amino steroids. 2. Energetics of the chair-twist-boat equilibrium in ring A of 3α-Hydroxy-2β-(4-morpholinyl)-5α(H)-androstan-17-one

The equilibrium between chair and twist-boat conformations in ring A of the title compound has been studied by variable solvent, high-field ¹H and ¹³C NMR. The distribution between chair and twist-boat forms was estimated from a consideration of vicinal ¹H coupling constants within the A ring and also the ¹³C chemical shift of a “marker group” (10-methyl) that was shown to be sensitive to the conformational change. A unique aspect of the study is that the population analysis was performed in such a way that the results are not dependent on a Karplus equation. The driving force for the transition from a chair conformation to a twist-boat was found to be a fine balance between steric effects, electronic effects, and hydrogen bonding. The energy difference between the chair and twist-boat forms is near zero and ranges from −1.1 to +1.2 kcal mol⁻¹, depending on the medium. The intramolecular hydrogen bond contributes approximately 1.5 kcal mol⁻¹ to the stability of the twist-boat conformation.