A practical guide to atropisomerism: fundamentals and case studies from modern drug discovery

Atropisomerism is a form of axial chirality that arises when rotation about a single bond is sufficiently restricted to render the enantiomeric conformers configurationally stable and isolable. Because bond rotation provides a spontaneous pathway for racemization, atropisomers span an extraordinary range of stereochemical stabilities-from species that racemize within seconds at room temperature to compounds predicted to retain their configuration for milenia under any pharmaceutically relevant conditions. Although atropisomerism is most commonly associated with biaryl scaffolds, it can arise across a remarkably diverse range of molecular architectures. Many of these have emerged as privileged pharmaceutical scaffolds, making atropisomerism an increasingly important consideration in medicinal chemistry, with more than 20 configurationally stable atropisomeric drug candidates currently in clinical development worldwide. Consequently, atropisomerism has evolved from a topic of primarily academic interest into a common and practical challenge in modern drug discovery and development. In this review, we discuss the challenges associated with the discovery, development, and manufacturing of atropisomeric drug candidates, culminating in a survey of the strategies used to establish atropisomeric axes on process scale for approved drugs and compounds currently undergoing clinical evaluation. We hope this review will serve as both a practical resource and a source of inspiration for chemists developing the next generation of atropisomerically pure pharmaceuticals.