Thiol-Yne click chemistry of acetylene-enabled macrocyclization

Thiol-yne coupling is a reliable method to link two molecular units, but has not been extensively explored for the construction of macrocycles. Here, the authors use gaseous acetylene, the simplest alkyne unit, to synthesize a variety of macrocycles under photocatalytic conditions. Macrocycles have fascinated scientists for over half a century due to their aesthetically appealing structures and broad utilities in chemical, material, and biological research. However, the efficient preparation of macrocycles remains an ongoing research challenge in organic synthesis because of the high entropic penalty involved in the ring-closing process. Herein we report a photocatalyzed thiol-yne click reaction to forge diverse sulfur-containing macrocycles (up to 35-membered ring) and linear C2-linked 1,2-(S-S/S-P/S-N) functionalized molecules, starting from the simplest alkyne, acetylene. Preliminary mechanistic experiments support a visible light-mediated radical-polar crossover dihydrothiolation process. This operationally straightforward reaction is also amenable to the synthesis of organometallic complexes, bis-sulfoxide ligand and a pleuromutilin antibiotic drug Tiamulin, which provides a practical route to synthesize highly valued compounds from the feedstock acetylene gas.

Automated summary

Thiol-yne coupling is a reliable method to connect two molecular units, and this study demonstrates its application in synthesizing diverse macrocycles using gaseous acetylene under photocatalytic conditions. The efficient synthesis of macrocycles is challenging in organic synthesis, but this photocatalyzed thiol-yne click reaction provides a practical route to forge diverse sulfur-containing macrocycles and functionalized molecules.