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. The tendence of some popular chiral drugs (endowed with tricyclic‐structures characterized by stereogenic‐plane) to underwent racemization by flipping of their chiral‐plane has been investigated by resorting to both experimental and theoretical approach. The obtained results suggested which structural modifications can be rationally designed in order to modulate their intrinsic stereolability, so allowing to suitably increase their enantiomerization barrier.