Confinement Catalysis Enables Macrocyclization at Up to 0.6 M: Selective Formation of Mono- and Dimeric Glycosidic Macrocycles.

Macrocyclic compounds are widespread in nature and frequently found among bioactive natural products. Their conformational preorganization allows them to effectively engage large binding surfaces, making them valuable in drug discovery, especially for modulating protein-protein interactions. Consequently, macrocyclization strategies have received significant attention; however, they still typically rely on high-dilution conditions (0.10-10 mM) to favor intramolecular ring closure over intermolecular oligomerization. Here, we report a solution to this long-standing challenge using a catalytic confined-space approach that operates efficiently even at the substrate solubility limit (600 mM), thereby eliminating the need for high-dilution conditions. The capsular catalyst enables the high-yielding formation of medium- and large-sized glycosidic macrocycles with excellent β-selectivity. Moreover, the method addresses a second persistent challenge in macrocyclization: the selective formation of macrocyclic dimers. Whereas such dimers are inaccessible under traditional high-dilution conditions, they are obtained in high yields when two substrates fit into the capsule's cavity, again at high substrate concentrations and with excellent β,β-selectivity. Control experiments establish the indispensability of the capsule as conventional conditions afford substantially lower yields and predominantly α-selectivity. The method's utility is further demonstrated in the selective synthesis of the dimeric core structure of glucolipsin A and cycloviracin B1. This work establishes confinement catalysis as a powerful tool to overcome key limitations in macrocyclization chemistry.