Total Synthesis of the Tiacumicin B (Lipiarmycin A3/Fidaxomicin) Aglycone |
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| Authors: | M. Sc. Florian Glaus Prof. Karl‐Heinz Altmann |
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| 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) |
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| 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. |
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| Keywords: | Corey– Peterson olefination macrolides Suzuki coupling tiacumicin total synthesis |
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