Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 136, Issue 34, Pages 12137-12160Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ja506472u
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Funding
- National Institutes of Health (USA) [AI055475, AI080714]
- Skaggs Institute of Research
- Cancer Prevention & Research Institute of Texas (CPRIT)
- Welch Foundation
- NSF Graduate Research Fellowship
- Feodor Lynen Research Fellowship
- Alexander von Humboldt Foundation
- Marie-Curie International Outgoing Fellowship
- European Commission
- Fundacion Alfonso Martin Escudero
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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.
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