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

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    Author
    Nicolaou, K.C.; Hale, Christopher R.H.; Nilewski, Christian; Ioannidou, Heraklidia A.; ElMarrouni, Abdelatif; More... Nilewski, Lizanne G.; Beabout, Kathryn; Wang, Tim T.; Shamoo, Yousif Less...
    Date
    2014
    Abstract
    The 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.
    Citation
    Nicolaou, 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." Journal of the American Chemical Society, 136, no. 34 (2014) American Chemical Society: 12137-12160. http://dx.doi.org/10.1021/ja506472u.
    Published Version
    http://dx.doi.org/10.1021/ja506472u
    Type
    Journal article
    Publisher
    American Chemical Society
    Citable link to this page
    https://hdl.handle.net/1911/77175
    Rights
    Article 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.
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    • Biochemistry and Cell Biology Publications [118]
    • Chemistry Publications [636]
    • EEB Faculty Publications [67]
    • Faculty Publications [4988]

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    Home | FAQ | Contact Us | Privacy Notice | Accessibility Statement
    Managed by the Digital Scholarship Services at Fondren Library, Rice University
    Physical Address: 6100 Main Street, Houston, Texas 77005
    Mailing Address: MS-44, P.O.BOX 1892, Houston, Texas 77251-1892
    Site Map