Non‐Dilute Synthesis of Macrodiolides and Macrotetrolides Enabled by Confinement Catalysis

Abstract

ABSTRACT 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.