Evaluation of the Stereochemical Lability of Benzo-Cycloheptene-Based Drugs Endowed with Potentially Modulable Planar Chirality

An experimental and theoretical study was carried out to analyze the configurational lability possessed by some of the most common drugs endowed with a central non-planar seven-membered cycloheptadiene ring, which confers chirality to these compounds. In fact, the absence of planarity allows the existence of two enantiomeric species that can interconvert thanks to a ring overturning mechanism. The energy barrier that opposes the inversion of the chiral tricyclic scaffold characterizing such species, which is strongly dependent on the presence of appropriate substituents on the two external cycles, has been investigated through Dynamic-HPLC and off-column racemization techniques, as well as through assessments based on molecular modelling approaches. Interesting indications were obtained by making targeted structural changes to allow accurate control of the stereolability characterizing the tricyclic framework.

Automated summary

An experimental and theoretical study was conducted to analyze the configurational lability of drugs with a non-planar seven-membered cycloheptadiene ring, which confers chirality to these compounds. The study investigated the energy barrier opposing the inversion of the chiral tricyclic scaffold, which is dependent on appropriate substituents on the external cycles. Structural changes were made to accurately control the stereolability of the tricyclic framework, providing interesting insights.