Total Synthesis of <i>iso</i> -Gladiolin Methyl Ester (Lagriene Methyl Ester) via Catalytic Asymmetric C–C Coupling of Alcohols

Gladiolin, a specialized metabolite of <i>Burkholderia gladioli</i>, is an antitubercular 22-membered macrolide that inhibits RNA polymerase at a site distinct from rifampicin, making it effective against drug resistant strains of Mtb. Lagriene is a 24-membered macrolide isolated from an alternate strain of <i>B. gladioli</i> and as demonstrated herein is the ring-expanded isomer of gladiolin, termed <i>iso</i>-gladiolin. Gladiolin is unstable with respect to isomerization to form the ring-expanded macrolide <i>iso</i>-gladiolin, suggesting that the biological activity of gladiolin may derive from <i>iso</i>-gladiolin. Here, we report the total synthesis of <i>iso</i>-gladiolin methyl ester via gladiolin methyl ester in 16 steps (LLS) using a quadruply convergent route, in which each fragment is prepared by catalytic asymmetric alcohol-mediated C-C coupling. Comparison of synthetic and natural <i>iso</i>-gladiolin methyl ester corroborates the assigned structure of both gladiolin and <i>iso</i>-gladiolin.