The stereocontrolled synthesis of naturally occurring products containing a 5,5-spiroketal molecular structure represents a major synthetic problem. Moreover, in a previous work, the stereocontrolled synthesis of cephalosporolide E (ceph E), which presumably was obtained from its epimer congener (ceph F) through an acid-mediated equilibration process, was reported. Consequently, we performed a theoretical investigation to provide relevant information regarding the title question, and it was found that the higher thermodynamic stability of ceph E, relative to ceph F, is caused by an n → π* interaction between a lone electron pair of the oxygen atom of the spiroketal ring (nO) and the antibonding orbital of the carbonyl group (π*C=O). Although similar stereoelectronic interactions have been disclosed in other molecular structures, its presence in ceph E, and very likely in other related naturally occurring products, represents a novel nonanomeric stabilizing effect that should be introduced into the chemical literature.