Total Synthesis of the Polyether Antibiotic Ionomycin

A convergent asymmetric synthesis of the calcium ionophore ionomycin has been achieved through a route that is outlined below. The four illustrated subunits, which comprise the C₁-C₁₀, C₁₁-C₁₆, C₁₇-C₂₂, and C₂₃-C₃₂ portions of ionomycin, were constructed through the use of chiral enolate bond constructions wherein 9 of the 14 stereogenic centers were created. The remaining chirality at C₆, C₂₁, C₂₆, C₃₀, and C₃₁ was incorporated through internal asymmetric induction. In the assemblage process, the ylide derived from the C₂₃-C₃₂ synthon was coupled with the C₁₇-C₂₂ aldehyde. The C₂₃-C₂₆ tetrahydrofuranyl ring and associated C₂₃ stereocenter were then established through intramolecular oxymercuration, which proceeded in a highly diastereoselective manner (≥93:7) with the desired stereochemical outcome. The C₁₆-C₁₇ double bond was constructed through a Julia trans olefination sequence. The union of the C₁-C₁₀ keto ester with the assembled C₁₁-C₃₂ aldehyde was achieved through an aldol bond construction. Subsequent oxidation of the C₁₁ alcohol afforded the fully protected ionomycin structure. Final deprotection provided synthetic ionomycin whose absolute configuration is in full agreement with that determined by X-ray crystallography.