Rules for Dibenzocyclooctadiene Conformational Dynamics

High Resolution Image Download MS PowerPoint Slide 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 13 C NMR signal broadening at several resonances in a series of new dibenzocyclooctadienes isolated from Kadsura heteroclita, (kadheterins I-K, 1 - 3 ). To understand this, we reviewed the 13 C 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.