Total Synthesis of the Guangnanmycin A Alcohol

Abstract

AbstractGuangnanmycin A is a recently discovered congener of the well‐known antitumor drug lead leinamycin; its macrolactam ring, however, is even more strained than that of the parent compound. The first synthetic foray towards this challenging target is reported, which relies on molybdenum‐catalyzed macrocyclization by ring closing alkyne metathesis (RCAM) followed by ruthenium‐catalyzed redox isomerization of the propargyl alcohol thus formed; the resulting enone enabled the introduction of the yet missing exo‐methylene group by a modified Peterson olefination. The signature disulfide moiety of guangnanmycin A was installed by strain‐driven thia‐Michael addition followed by conversion of the thioether thus formed into an unsymmetric disulfide with the aid of (methylthio)dimethylsulfonium tetrafluoroborate and MeSSMe. While this sequence furnished racemic guangnanmycin A alcohol in good overall yield, the final oxidation to the corresponding acid failed, most likely because of the exceptional sensitivity of the strained scaffold.