AbstractAn extensive and systematic conformational search was performed on the two epimers of the natural lignan 7‐hydroxymatairesinol (HMR), by means of a home‐made Systematic Conformational Search Analysis (SCSA) code, designed to select more and more stable conformers through sequential geometry optimization of trial structures at increasing levels of calculation theory. In the present case, the starting molecular structures were selected by the semi‐empirical AM1 method and filtered – i.e. decreased in number by choosing the more stable species – on the basis of their energy calculated by the HF method and the 6‐31G(d) basis set. The geometries obtained were further refined by performing density functional theory (DFT) optimizations, using the B3LYP functional and the 6‐31G(d,p) basis set, both in vacuo and in ethanol solution. This procedure allowed us to isolate, at a high level of theory, three groups of epimer conformers characterized by open, semi‐folded, and folded conformations. Moreover, the SCSA allowed us to describe a conformational space made‐up by about 20 species for each of the two epimers. The corresponding energy content of these species was within 27 kJ mol−1 from the absolute minimum found, both in vacuo and in ethanol solution. The conformational analysis, followed by the inspection of the stereochemistry of the two most stable conformers of both epimers, provides support in rationalizing the proposed reaction mechanism of the catalytic hydrogenolysis of the HMR to matairesinol (MAT). Copyright © 2009 John Wiley & Sons, Ltd.