Progress towards viridin: synthesis of the pentacyclic furanosteroid ring system via o-benzoquinonoid cycloadditions

Souza, Fabio E. S.; Rodrigo, R.

doi:10.1039/a905731e

Cited by 22 publications

(18 citation statements)

References 14 publications

(10 reference statements)

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“…With potential as therapeutic agents for the treatment of neoplasms and other diseases,12 viridin and its relatives provide prime targets for research in organic synthesis. Although a total synthesis of viridin has not yet been reported, Shibasaki and co‐workers reported an impressive synthesis of the complex furanosteroid wortmannin ( 2 )13 and Souza and Rodrigo described a creative route to the pentacyclic core of viridin ( 1 ) 14. Herein we report the first total synthesis of racemic viridin ( 1 ; Scheme ).…”

Section: Methodsmentioning

confidence: 93%

Synthesis of the Furanosteroidal Antibiotic Viridin

2004

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Among the natural products that modulate protein function with high selectivity, [1] there is a group of reactive molecules that alkylate nucleophilic residues in the active sites of important enzymes. Lipstatin, [2] fumagillin, [3] and microcystin [4] embody the chemistry of the carbonyl group, the epoxide, and the electron-deficient alkene, respectively, and are prominent examples of protein-reactive natural products. These and related secondary metabolites are important because they have yielded insight into the cellular functions of key enzymes and will likely prove invaluable as molecular probes in protein-activity-profiling experiments. [5] Our interest in research opportunities provided by natural products that covalently inhibit protein function [6] induced us to address the chemical problem posed by viridin (1) [7] (Scheme 1), a potent antifungal metabolite of Gliocladium virens and the parent member of a family of furanosteroids that includes wortmannin (2), viridiol, and demethoxyviridin.[8] These natural products are biosynthesized from the triterpene lanosterol and are distinguished by an unusual structural feature: an electron-deficient furan ring fused between C4 and C6 of the steroid framework. The doubly activated carbon atom of this heterocycle predisposes these compounds to react efficiently with a range of amines, [9] including the active-site lysine of phosphatidylinositol 3-kinase (PI 3 -kinase).[10] Wortmannin (2) and demethoxyviridin are potent and relatively selective covalent inhibitors of PI 3 -kinase [11] and have served as valuable molecular tools for deciphering the role of PI 3 -kinase in signal-transduction pathways.With potential as therapeutic agents for the treatment of neoplasms and other diseases, [12] viridin and its relatives provide prime targets for research in organic synthesis.

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Section: Methodsmentioning

confidence: 93%

Synthesis of the Furanosteroidal Antibiotic Viridin

2004

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“…14,27,28 Afterwards, the naphthalene portion was appended through the cycloaddition of an electron-rich isobenzofuran.…”

Section: Total Syntheses Of Halenaquinol Xestoquinol and Thiohalmentioning

confidence: 99%

Strategies for the Synthesis of the Halenaquinol and Xestoquinol Families of Natural Products

Schwarzwalder

Vanderwal

2017

Eur J Org Chem

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The halenaquinol family of naphthoquinol natural products includes a few closely related polycyclic compounds that feature an activated, electrophilic furan ring. This motif is likely responsible for the rich biological activity attributed to these secondary metabolites. Their interesting structures—related via their electrophilic furan to the biologically important furanosteroids—and their activities prompted significant efforts by organic chemists that resulted in many strategically compelling laboratory syntheses of these targets. These different strategies are compared and contrasted in this Microreview, and the authors’ recent work on the structurally different but biogenetically related natural product exiguaquinol is put into the context of the previous studies on halenaquinol-type targets.

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“…In addition to wortmannin, related natural products have also served as target molecules for the development of innovative synthetic strategies. A synthesis of the core of viridin (5) was published by Souza and Rodrigo, 40 and a total synthesis of this target was recently accomplished by Anderson, Alexanian and Sorensen. 41 Several protocols for the preparation of xestoquinone and halenaquinone have appeared (vide infra).…”

Section: Synthetic Approaches Toward Wortmanninmentioning

confidence: 99%

“…41 Several protocols for the preparation of xestoquinone and halenaquinone have appeared (vide infra). 10,42 In addition to the accomplishments of Shibasaki 37, 38 and Broka and coworkers, 39 Rodrigo's partial synthesis of viridin 40 and the total syntheses of 2 and 5 will be discussed in more detail. 42a…”

Section: Synthetic Approaches Toward Wortmanninmentioning

confidence: 99%

Chemistry and biology of wortmannin

2005

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Recent synthetic and biological studies of the viridin class of steroidal furans have revealed multiple opportunities for fundamental discoveries as well as advanced drug design. Wortmannin is a potent enzyme inhibitor that binds to the ATP site of important regulatory kinases such as PI-3 kinase and Polo-like kinase. The natural product shares a unique mechanism-based biological activation pathway with other viridins. Furthermore, while there have been several encouraging approaches toward the total synthesis of these compounds, there is still ample room for improvements in synthetic strategies and tactics, and the development of structurally simplified analogs that exert more specific biological effects and are devoid of toxicity issues that have thwarted the clinical development of the parent compounds.

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Progress towards viridin: synthesis of the pentacyclic furanosteroid ring system via o-benzoquinonoid cycloadditions

Cited by 22 publications

References 14 publications

Synthesis of the Furanosteroidal Antibiotic Viridin

Synthesis of the Furanosteroidal Antibiotic Viridin

Strategies for the Synthesis of the Halenaquinol and Xestoquinol Families of Natural Products

Chemistry and biology of wortmannin

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