Rules for Dibenzocyclooctadiene Conformational Dynamics

The conformational dynamics of flexible compounds can meaningfully influence their NMR spectra and biological activities, yet these effects are easily overlooked. The dibenzocyclooctadiene lignans provide a clear example of this. Although >350 naturally occurring dibenzocyclooctadienes have been published, discrete spectral features have gone unnoticed, and misconceptions about their conformational dynamics pervade the literature. Our attention was drawn to this after observing ¹³C NMR signal broadening at several resonances in a series of new dibenzocyclooctadienes isolated from <i>Kadsura heteroclita</i>, (kadheterins I-K, <b>1</b>-<b>3</b>). To understand this, we reviewed the ¹³C NMR spectra of 71 published dibenzocyclooctadienes and found that >70% displayed the same broadening, yet the underlying cause had not been clearly rationalized. Systematic analysis revealed that this broadening is associated with key benzylic substituents at C-6. Computational and VT-NMR analyses revealed that these introduce destabilizing steric interactions in the twist-boat chair (TBC) conformation, promoting exchange with the less stable twist-boat (TB). In contrast, certain substituents (e.g., at C-7/C-8) were found to stabilize the TBC. Therefore, many dibenzocyclooctadienes previously described as adopting discrete TB/TBC conformers are interconverting mixtures. We have condensed our observations into a set of rules that predict how common substituents affect ring dynamics in this class of compounds.