Strategies for the Synthesis of Enantiopure Mechanically Chiral Molecules

Mechanically interlocked molecules, such as rotaxanes and catenanes, are composed of two or more covalent subcomponents threaded through one another such that they cannot be separated without breaking a covalent bond. This arrangement can allow the covalent subcomponents to undergo large-amplitude relative motion, and this property of the mechanical bond has been widely exploited in the design and synthesis of molecular machines. Another less well-known property of the mechanical bond is that it can give rise to chirotopic stereogenic units that do not rely on covalent stereogenic elements. Although the study of such “mechanically chiral” molecules is expanding, their synthesis in enantiopure form remains challenging. In this Perspective, we review the strategies available, highlighting key examples along the way, and suggest future areas for development. • Mechanically chiral molecules, structures that display dynamic or static molecular chirality in the absence of conventional covalent stereogenic elements, have many potential applications (e.g., in catalysis), but their synthesis in an enantiopure form remains challenging. • The incorporation of additional covalent stereogenic units into interlocked structures can bias the mechanical stereogenic unit and facilitate highly stereoselective syntheses, but studies of the applications of mechanical chirality will first require the synthesis of purely mechanically chiral molecules to demonstrate the role of the mechanical bond. • The application of modern enantioselective synthetic techniques to this challenge is now beginning to facilitate the scalable synthesis of mechanically chiral molecules. Interlocked, or “mechanically bonded,” molecules (such as rotaxanes and catenanes) can exhibit chirotopic stereogenic units that do not rely on covalent stereogenic elements. Although the study of such “mechanically chiral” molecules is expanding, their synthesis in enantiopure form remains challenging. In this Perspective, we discuss the synthesis of enantioenriched and enantiopure mechanically chiral molecules organized according to the classes of synthetic strategy typically discussed in covalent synthesis.