title: Total synthesis of viridicatumtoxin B and analogues thereof: strategy evolution, structural revision, and biological evaluation.
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.
authors.affiliation: Department of Chemistry, §Department of Biochemistry and Cell Biology, and ∥Department of Ecology and Evolutionary Biology, Rice University , 6100 Main Street, Houston, Texas 77005, United States.
authors.forename: K C
authors.initials: KC
authors.lastname: Nicolaou
authors.forename: Christopher R H
authors.initials: CR
authors.lastname: Hale
authors.forename: Christian
authors.initials: C
authors.lastname: Nilewski
authors.forename: Heraklidia A
authors.initials: HA
authors.lastname: Ioannidou
authors.forename: Abdelatif
authors.initials: A
authors.lastname: ElMarrouni
authors.forename: Lizanne G
authors.initials: LG
authors.lastname: Nilewski
authors.forename: Kathryn
authors.initials: K
authors.lastname: Beabout
authors.forename: Tim T
authors.initials: TT
authors.lastname: Wang
authors.forename: Yousif
authors.initials: Y
authors.lastname: Shamoo
mesh_terms: D000478:Alkylation; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D058116:Lewis Acids / Q000737:chemistry; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013754:Tetracyclines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D058116:Lewis Acids; D013754:Tetracyclines; C539435:viridicatumtoxin B