A Platform Approach to Cleavable Macrocycles for the Controlled Disassembly of Mechanically Caged Molecules

Inspired by interlocked oligonucleotides, peptides and knotted proteins, synthetic systems where a macrocycle cages a bioactive species that is “switched on” by breaking the mechanical bond have been reported. However, to date, each example uses a bespoke chemical design. Here we present a platform approach to mechanically caged structures wherein a single macrocycle precursor is diversified at a late stage to include a range of trigger units that control ring opening in response to enzymatic, chemical, or photochemical stimuli. We also demonstrate that our approach is applicable to other classes of macrocycles suitable for rotaxane and catenane formation. A mechanical lock with many keys. We show that a single macrocyclic precursor can be converted to self‐immolative macrocycles that open in response to enzymatic, chemical, or photochemical stimuli. Rotaxanes and catenanes based on these rings can be triggered to release their interlocked partner. This simple macrocycle platform can be used to accelerate the development of mechanically caged molecules.