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Total synthesis of viridicatumtoxin B and analogues thereof: strategy evolution, structural revision, and biological evaluation

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Overview

related to degree

  • Hale, Christopher (Kit) R H, Ph.D., Scripps Research 2009 - 2014

authors

  • Nicolaou, K.C.
  • Hale, Christopher (Kit) R H
  • Nilewski, C.
  • Ioannidou, H. A.
  • ElMarrouni, A.
  • Nilewski, L. G.
  • Beabout, K.
  • Wang, T. T.
  • Shamoo, Y.

publication date

  • August 2014

journal

  • Journal of the American Chemical Society  Journal

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.

subject areas

  • Alkylation
  • Anti-Bacterial Agents
  • Gram-Negative Bacteria
  • Gram-Positive Bacteria
  • Lewis Acids
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Tetracyclines
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Identity

PubMed Central ID

  • PMC4210137

International Standard Serial Number (ISSN)

  • 0002-7863

Digital Object Identifier (DOI)

  • 10.1021/ja506472u

PubMed ID

  • 25317739
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Additional Document Info

start page

  • 12137

end page

  • 12160

volume

  • 136

issue

  • 34

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