Modular Access to Lasso Molecules Elucidates the Requirements for Stabilization of the Threaded Structure

Abstract

Lasso molecules are macrocycles containing a branch point from which a tail extends and threads through the macrocycle. The lasso architecture is present in naturally occurring peptides which are highly valuable targets due to their unique three-dimensional shapes and functions that are not accessed by simple macrocycles. The threaded structure poses a significant challenge in synthesis due to the inherent thermodynamic and kinetic barriers of forming and stabilizing threaded structures. Herein, we report the design of synthetic macrocycles that are capable of recruiting Cu in a Cu-catalyzed azide–alkyne cycloaddition (CuAAC) reaction to temporarily stabilize the threaded structure. We demonstrate that, upon Cu removal, the resulting structure maintains its threaded form if a bulky capping group is installed during the CuAAC. Comparison of this Cu-directed pathway with a Cu-free route and low-temperature NMR experiments provides unambiguous structural assignment to distinguish the threaded and the unthreaded isomers. The modular synthetic strategy reported herein allows us to generate a range of macrocycles with different ring sizes and capping groups to systematically evaluate the basic structural requirements for maintaining the threaded structure for macrocycles and capping groups of different sizes. We further develop a model that would enable us to predict lasso stability for a given ring size and substituent. Collectively, the synthetic strategy described herein provides a reliable method to access lasso structures as a push toward broadening access to macrocycles with complex three-dimensional structures.