Total Synthesis of the Guangnanmycin A Alcohol

Abstract

Guangnanmycin 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 a molybdenum catalyzed macrocyclization by ring closing alkyne metathesis (RCAM) followed by a ruthenium catalyzed redox isomerization of the propargyl alcohol thus formed; the resulting enone served the introduction of the yet missing exo‐methylene group by a modified Peterson olefination well. The signature disulfide moiety of guangnanmycin A was installed by a 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 likely because of the exceptional sensitivity caused by the strained scaffold.