Modular Assembly of Macrocyclic Sulfonamides via Consecutive Cascade Ring Expansion Reactions

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Chemical Biology

Background:

• Sulfur(IV) compounds and macrocycles are crucial in medicinal chemistry.
• Efficient synthesis methods for macrocyclic sulfur(IV) compounds are limited.

Purpose of the Study:

• To develop a versatile and modular strategy for synthesizing macrocyclic sulfonamides.
• To address the scarcity of efficient methods for creating these important molecular structures.

Main Methods:

• A novel strategy employing consecutive ring expansion reactions.
• Assembly of linear starting materials from simple building blocks.
• Sequential execution of two distinct cascade ring expansion steps.

Main Results:

• Successful synthesis of a library of 42 diversely functionalized 13- and 14-membered macrocyclic sulfonamides.
• Demonstration of the modular approach's utility and versatility.
• Good overall yields achieved without high-dilution conditions.

Conclusions:

• Consecutive ring expansions are key to efficiently synthesizing macrocyclic sulfonamides.
• This protocol provides a valuable new tool for medicinal chemistry research.
• The method enables access to complex sulfur(IV) macrocycles.