Non-Dilute Synthesis of Macrodiolides and Macrotetrolides Enabled by Confinement Catalysis.

Macrodiolides are widespread motifs in functional molecules, yet their synthesis remains challenging. Existing methods typically still rely on high-dilution conditions to suppress undesired oligomerization, limiting efficiency and scalability. Therefore, developing macrocyclization strategies under non-dilute conditions remains a long-standing goal. Herein, we report a confinement approach to address this challenge by utilizing the spatial restriction and conformational preorganization provided by the hexameric resorcin[4]arene capsule. Such supramolecular confinement enables the cyclization of readily accessible diols and diacyl chlorides to afford 18-32-membered macrodiolides under non-dilute conditions and without the need for slow-addition procedures. Notably, the method also enables the one-pot formation of 26-32-membered macrotetrolides, a transformation that is difficult to achieve using conventional strategies, including high-dilution conditions. Compared with established ring-closing metathesis, this strategy offers higher efficiency, shorter synthetic routes, and access to more strained macrodiolides. Overall, these findings highlight the power of confinement catalysis for challenging macrocyclization reactions.