Enantiocontrolled macrocyclization by encapsulation of substrates in chiral capsules

Chiral macrocycles are commonly found in nature and have strong binding affinity to their targets. Thus, the development of efficient macrocyclization strategies is an important goal in the synthetic community. However, macrocyclization with chirality induction remains a great challenge because of the large entropic penalty associated with ring closure while maintaining the chiral conformation. Here, we report a highly efficient chiral macrocyclization with controlling enantioselectivity using a chiral confinement strategy. A linear substrate is encapsulated by a host precursor molecule through the formation of chiral capsule structures, which subsequently self-assemble into a robust two-dimensional structure entrapping the substrate with a folded chiral conformation. Then, the reaction under confinement generates an enantiopure macrocycle product. Furthermore, the chirality of the capsule assembly can switch into an opposite form using sonication, capable of controlling enantioselectivity. The substrate-encapsulating process is amenable to a substrate change, thus enabling diverse chirality induction in macrocycle formation. This macrocyclization method works with substrates decorated with a wide range of functional groups at high levels of precision and efficiency. Macrocyclization with chirality induction is challenging owing to the entropic penalty associated with ring closure while maintaining chiral conformation. Now, a confinement strategy is reported to achieve chiral macrocyclization and yield an enantiopure product. The chirality of the capsule can be switched to the opposite form by sonication.