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Total synthesis of the protected aglycon of fidaxomicin (Tiacumicin B, Lipiarmycin A3)


Miyatake-Ondozabal, Hideki; Kaufmann, Elias; Gademann, Karl (2015). Total synthesis of the protected aglycon of fidaxomicin (Tiacumicin B, Lipiarmycin A3). Angewandte Chemie Internationale Edition, 54(6):1933-1936.

Abstract

Fidaxomicin, also known as tiacumicin B or lipiarmycin A3, is a novel macrocyclic antibiotic that is used in hospitals for the treatment of Clostridium difficile infections. This natural product has also been shown to have excellent bactericidal activity against multidrug-resistant Mycobacterium tuberculosis. In spite of its attractive biological activity, no total synthesis has been reported to date. The enantioselective synthesis of the central 18-membered macrolactone is reported herein. The key reactions include ring-closing metathesis between a terminal olefin and a dienoate moiety for macrocyclization, a vinylogous Mukaiyama aldol reaction, and a Stille coupling reaction of sterically demanding substrates. The retrosynthesis involves three medium-sized fragments, thus leading to a flexible yet convergent synthetic route.

Abstract

Fidaxomicin, also known as tiacumicin B or lipiarmycin A3, is a novel macrocyclic antibiotic that is used in hospitals for the treatment of Clostridium difficile infections. This natural product has also been shown to have excellent bactericidal activity against multidrug-resistant Mycobacterium tuberculosis. In spite of its attractive biological activity, no total synthesis has been reported to date. The enantioselective synthesis of the central 18-membered macrolactone is reported herein. The key reactions include ring-closing metathesis between a terminal olefin and a dienoate moiety for macrocyclization, a vinylogous Mukaiyama aldol reaction, and a Stille coupling reaction of sterically demanding substrates. The retrosynthesis involves three medium-sized fragments, thus leading to a flexible yet convergent synthetic route.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Uncontrolled Keywords:antibiotics; cross coupling; natural products; stereoselective synthesis
Language:English
Date:2 February 2015
Deposited On:22 Aug 2017 16:28
Last Modified:23 Aug 2017 07:33
Publisher:Wiley-VCH Verlag
ISSN:1433-7851
Publisher DOI:https://doi.org/10.1002/anie.201409464
PubMed ID:25431322

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