Modular Assembly of Macrocyclic Sulfonamides via Consecutive Cascade Ring Expansion Reactions

Sulfur(IV) groups and macrocycles are both important motifs in bioactive molecules of significant current interest in medicinal chemistry, but methods for the efficient synthesis of macrocyclic sulfur(IV) compounds are rare. In this manuscript, a modular, versatile strategy for the synthesis of macrocyclic sulfonamides is described, using consecutive ring expansion reactions. First, linear starting materials are assembled from simple building blocks. This is followed by two distinct cascade ring expansion reaction steps performed in sequence. The utility of this modular approach is showcased via the synthesis of a library of 42 diversely functionalized 13- and 14-membered macrocyclic sulfonamides. The use of consecutive ring expansions is key to the success of the protocol, ensuring the products are formed in overall good yields without requiring high-dilution conditions.