Deep Cavitand Mediated Selective Aerobic Oxidative Cyclization of Thiols to Cyclic Disulfides

Abstract

A mild supramolecular template strategy is reported for the selective synthesis of medium- to macrocyclic disulfides via aerobic oxidative cyclization of α,ω-dithiols in aqueous media. The water-soluble deep cavitand CV-1 serves as a multifunctional platform that synergistically addresses challenges of aqueous-phase macrocyclization, including poor substrate solubility, low cyclization selectivity, and unproductive side reactions of reactive intermediates. Specifically, CV-1 enables solubilization of hydrophobic linear α,ω-dithiols in water, preorganizes them into folded J-shaped conformations favorable for intramolecular coupling, and sequesters reactive thiyl radical (RS·) intermediates within its confined cavity to suppress oligomerization. This interplay allows efficient aerobic oxidative cyclization under mild, metal-free conditions with ambient air as the sole oxidant, affording 8- to 14-membered cyclic disulfides in 61–89% yields. The cavitand cavity provides enduring stabilization of the encapsulated disulfide bonds, rendering them inert toward strong external reductants such as dithiothreitol (DTT). This work provides a preliminary demonstration of supramolecularly controlled macrocyclization in water, offering insights for future applications in biochemistry, pharmaceuticals, and materials science.