Total Synthesis of Tiacumicin†B: Implementing Hydrogen Bond Directed Acceptor Delivery for Highly Selective ß-Glycosylations.

A total synthesis of tiacumicin B, a natural macrolide whose remarkable antibiotic properties are used to treat severe intestinal infections, is reported. The strategy is in part based on the prior synthesis of the tiacumicin B aglycone, and on the decisive use of sulfoxides as anomeric leaving groups in hydrogen-bond-mediated aglycone delivery (HAD). This new HAD variant permitted highly ß-selective rhamnosylation and noviosylation. To increase convergence, the rhamnosylated C1-C3 fragment thus obtained was anchored to the C4-C19 aglycone fragment by adapting the Suzuki-Miyaura cross-coupling used for the aglycone synthesis. Ring-size-selective macrolactonization provided a compound engaged directly in the noviolysation step with virtually total ß selectivity. The final efficient removal of all the protecting groups provided synthetic tiacumicin B.

Synthesis of a Tiacumicin B Protected Aglycone.

Tiacumicin B is an antibiotic endowed with the remarkable ability to interact with a new biological target, giving it an inestimable potential in the context of the ever-growing and worrisome appearance of resistances of bacteria and mycobacteria to antibiotics. The synthesis of an aglycone of tiacumicin B ready for glycosylation is reported. The key steps of this approach are a [2,3]-Wittig rearrangement, a Pd/Cu-catalyzed allene-alkyne cross-coupling, a E-selective cross-metathesis, and a final ring-size selective macrolactonization.