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
synthesis, Mycobacterium tuberculosis, Clostridium difficile, tiacumicin, Dactylosporangium aurantiacum
NCBI PubMed ID: 25510439Publication DOI: 10.1002/anie.201409510Journal NLM ID: 0370543Publisher: Weinheim: Wiley-VCH
Correspondence: karl-heinz.altmann@pharma.ethz.ch
Institutions: Swiss Federal Institute of Technology (ETH) Zürich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, HCI H405, Zürich, Switzerland
Methods: chemical synthesis, HPLC
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