Mechanisms and pharmaceutical consequences of processes of stereoisomerisation - A didactic excursion

Abstract

This writing proposes an overview of chemical processes of isomerisation involving conformations and configurational isomers. Molecular structure is depicted as consisting in A) core features; and B) fluctuating properties. To avoid confusion and misuses in terminology, attention is paid to IUPAC recommendations and definitions, beginning with a focus on conformers versus conformations. Two sections consider rotations, the behaviour of exocyclic single bonds being kept separate from that of endocyclic single bonds. Processes of pyramidal inversions are discussed next, alone and combined with rotations. Given its sometimes unsuspected occurrence in some drug molecules, stereolability at tetracoordinated carbon centres receives particular attention. Stereolabile and stereostable nitrogen-containing groups come next, with a focus on the simultaneous contributions of inversion and rotation as occurring for example in the conformational reversal of saturated aza-heterocycles. The last type of isomerisation to be examined involves complex heterocyclic systems of medicinal relevance. The conclusion points to the mechanistic variety of stereoisomerisation processes, to a continuum in their energy barriers, to their relevance in all fields of stereochemistry, and to the need for junior medicinal chemists to be adequately trained in stereochemistry.

Keywords: Amfepramone; Benzodiazepines; Bond rotation; Cathinone; Chiral inversion; Chirality; Configuration; Conformation; Free energy; Gossypol; Hyoscyamine and atropine; Ketotifen; Lidocaine; Peptides; Pilocarpine; Stereoselectivity; Telenzepine.