Direct Active Template Synthesis of Cyclic Peptide Catenanes

Synthesising mechanically interlocked molecules in which one of the components is a cyclic peptide is a longstanding challenge in synthetic supramolecular chemistry, inspired in no small part by the intriguing biological properties of lasso peptides, which contain this motif. However, to date, reported methods to access interlocked cyclic peptides make use of highly engineered polyproline macrocycles with non-peptide linear partners, as cyclic peptides more generally are poor hosts for either active or passive template mechanical bond forming methodologies. Unfortunately, even in these optimised cases the yields obtained are typically low and the cyclic peptide component has minimal structural diversity. Here, we show that reversing this standard strategy, by forming the peptide macrocycle in the mechanical bond forming step itself using an active template reaction, is a general solution to the synthesis of cyclic peptide catenanes. Furthermore, we show that the mechanical bond controls the conformational flexibility of the cyclic peptide, enhances its stability to proteolysis, and modulates its lipophilicity, all key parameters for biological applications. Our approach thus opens the way to mechanically engineering the properties of biologically relevant cyclic peptides.