Formal synthesis of tubelactomicins via a transannular Diels-Alder approach

A formal synthesis of the antimicrobial tricyclic macrolides, tubelactomicins A and E, featured by a transannular Diels-Alder (TADA) approach, has been explored. The key issue for the transannular cyclization was the synthesis of a 24-membered macrolactone equipped with all the requisite functionalities, which has been achieved using an intramolecular Hiyama cross-coupling strategy. The Hiyama coupling reaction spontaneously triggered off the TADA reaction. From the endo-TADA adduct, formal syntheses of tubelactomicins A and E were achieved. The 24-membered macrolactone formation was also achieved via an intramolecular ring-closing metathesis approach.