Copper-Templated Coupling

In 2000, Jiri Srogl and Lanny S. Liebeskind of Emory University reported a unique coupling of thiol esters with boronic acids to produce ketones. That reaction, mediated by a palladium catalyst and a stoichiometric copper cocatalyst, operates at neutral pH and in the absence of oxygen to protect sensitive functional groups. Srogl, Liebeskind, and Janette M. Villalobos have now determined that the same reaction can be carried out under aerobic conditions without a palladium catalyst (J. Am. Chem. Soc., DOI: 10.1021/ja074931n). The key is formation of a Cu(I)-thiol ester complex, which is oxidized by O₂ in the air to form a Cu(II/III) intermediate. This intermediate serves as a template for the thiol ester-boronic acid coupling to form a ketone. The residual copper thiolate complex reacts with a second equivalent of boronic acid to form a thioether, a process that regenerates the starting Cu(I) complex and completes the catalytic cycle. So far, the Emory team has synthesized peptidyl ketones, in addition to the reported 1:1 mixtures of ketones and thioethers.