Total Synthesis of Viridicatumtoxin B and Analogues Thereof: Strategy Evolution, Structural Revision, and Biological Evaluation

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dc.citation.firstpage12137en_US
dc.citation.issueNumber34en_US
dc.citation.journalTitleJournal of the American Chemical Societyen_US
dc.citation.lastpage12160en_US
dc.citation.volumeNumber136en_US
dc.contributor.authorNicolaou, K.C.en_US
dc.contributor.authorHale, Christopher R.H.en_US
dc.contributor.authorNilewski, Christianen_US
dc.contributor.authorIoannidou, Heraklidia A.en_US
dc.contributor.authorElMarrouni, Abdelatifen_US
dc.contributor.authorNilewski, Lizanne G.en_US
dc.contributor.authorBeabout, Kathrynen_US
dc.contributor.authorWang, Tim T.en_US
dc.contributor.authorShamoo, Yousifen_US
dc.date.accessioned2014-09-12T17:46:11Zen_US
dc.date.available2014-09-12T17:46:11Zen_US
dc.date.issued2014en_US
dc.description.abstractThe details of the total synthesis of viridicatumtoxin B (1) are described. Initial synthetic strategies toward this intriguing tetracycline antibiotic resulted in the development of key alkylation and Lewis acid-mediated spirocyclization reactions to form the hindered EF spirojunction, as well as Michael-Dieckmann reactions to set the A and C rings. The use of an aromatic A-ring substrate, however, was found to be unsuitable for the introduction of the requisite hydroxyl groups at carbons 4a and 12a. Applying these previous tactics, we developed stepwise approaches to oxidize carbons 12a and 4a based on enol- and enolate-based oxidations, respectively, the latter of which was accomplished after systematic investigations that revealed critical reactivity patterns. The herein described synthetic strategy resulted in the total synthesis of viridicatumtoxin B (1), which, in turn, formed the basis for the revision of its originally assigned structure. The developed chemistry facilitated the synthesis of a series of viridicatumtoxin analogues, which were evaluated against Gram-positive and Gram-negative bacterial strains, including drug-resistant pathogens, revealing the first structure-activity relationships within this structural type.en_US
dc.identifier.citationNicolaou, K.C., Hale, Christopher R.H., Nilewski, Christian, et al.. "Total Synthesis of Viridicatumtoxin B and Analogues Thereof: Strategy Evolution, Structural Revision, and Biological Evaluation." <i>Journal of the American Chemical Society,</i> 136, no. 34 (2014) American Chemical Society: 12137-12160. http://dx.doi.org/10.1021/ja506472u.en_US
dc.identifier.doihttp://dx.doi.org/10.1021/ja506472uen_US
dc.identifier.urihttps://hdl.handle.net/1911/77175en_US
dc.language.isoengen_US
dc.publisherAmerican Chemical Societyen_US
dc.rightsArticle is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.en_US
dc.titleTotal Synthesis of Viridicatumtoxin B and Analogues Thereof: Strategy Evolution, Structural Revision, and Biological Evaluationen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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