Total Synthesis of iso-Gladiolin Methyl Ester (Lagriene Methyl Ester) via Catalytic Asymmetric C-C Coupling of Alcohols.

Gladiolin, a specialized metabolite of Burkholderia gladioli, 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 B. gladioli and as demonstrated herein is the ring-expanded isomer of gladiolin, termed iso-gladiolin. Gladiolin is unstable with respect to isomerization to form the ring-expanded macrolide iso-gladiolin, suggesting that the biological activity of gladiolin may derive from iso-gladiolin. Here, we report the total synthesis of iso-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 iso-gladiolin methyl ester corroborates the assigned structure of both gladiolin and iso-gladiolin.