title: Total synthesis of the tiacumicin B (lipiarmycin A3/fidaxomicin) aglycone.
abstract: Tiacumicin B (lipiarmycin A3, fidaxomicin) is an atypical macrolide antibiotic which is used for the treatment of Clostridium difficile infections. Tiacumicin B is also a potent inhibitor of Mycobacterium tuberculosis, but due to its limited oral bioavailability is unsuitable for systemic therapy. To provide a basis for structure-activity studies that might eventually lead to improved variants of tiacumicin B, we have developed an efficient approach to the synthesis of the tiacumicin B aglycone. The synthesis features a high-yielding intramolecular Suzuki cross-coupling reaction to effect macrocyclic ring closure. Key steps in the synthesis of the macrocyclization precursor were a highly selective, one-pot Corey-Peterson olefination and an ene-diene cross-metathesis reaction. Depending on the reaction conditions, the final deprotection delivered either the fully deprotected tiacumicin B aglycone or partially protected versions thereof.
authors.affiliation: Swiss Federal Institute of Technology (ETH) Zürich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, HCI H405, Vladimir-Prelog-Weg 4, 8093 Zürich (Switzerland).
authors.forename: Florian
authors.initials: F
authors.lastname: Glaus
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Altmann
mesh_terms: D000617:Aminoglycosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D000077732:Fidaxomicin
chemical_list: D000617:Aminoglycosides; D000077732:Fidaxomicin
keywords: Corey-Peterson olefination; Suzuki coupling; macrolides; tiacumicin; total synthesis