Total Synthesis of (±)-Nisamycin.

Abstract

We have developed a highly convergent synthesis of the manumycin-type m-C7N-antibiotic nisamycin that is applicable to other members of this family of antibiotics. The synthesis features a three-step sequence to the epoxyquinol core that serves as a scaffold for the attachment of the polyene side chains. The eastern polyene side chain was constructed via a novel organozirconocene-mediated synthesis. Zirconocene methodology was also applied to the synthesis of the polyene side chains of asukamycin. The southern side chain of nisamycin was introduced via a Stille reaction that employed a vinyl bromo ketone, derived from an acid-sensitive bromo ketal. Pd-mediated coupling of the vinyl bromide with a stannyl TIPS ester gave TIPS-protected nisamycin that was readily converted to the natural product.