# Rules for Dibenzocyclooctadiene Conformational Dynamics

## TL;DR

This paper explains how substituents on dibenzocyclooctadiene compounds influence their conformational dynamics, affecting NMR spectra and biological activity.

## Contribution

The study establishes rules predicting how substituents affect conformational dynamics in dibenzocyclooctadiene lignans.

## Key findings

- Key benzylic substituents at C-6 destabilize the twist-boat chair conformation, promoting exchange with the twist-boat conformation.
- Certain substituents at C-7/C-8 stabilize the twist-boat chair conformation.
- Many previously described conformers are actually interconverting mixtures.

## Abstract

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 Kadsura heteroclita, (kadheterins I-K, 1-3). 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.