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

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• 作者：K. C. Nicolaou ; Christopher R. H. Hale ; Christian Nilewski ; Heraklidia A. Ioannidou ; Abdelatif ElMarrouni ; Lizanne G. Nilewski ; Kathryn Beabout ; Tim T. Wang ; Yousif Shamoo
• 刊名：Journal of the American Chemical Society
• 出版年：2014
• 出版时间：August 27, 2014
• 年：2014
• 卷：136
• 期：34
• 页码：12137-12160
• 全文大小：1960K
• ISSN：1520-5126

文摘

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鈥揇ieckmann 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鈥揳ctivity relationships within this structural type.