Synthesis of the 10-oxabicyclo[5.2.1]decane framework present in bioactive natural products

Ángel M. Montaña, Stefano Ponzano, Maria Filomena Sanasi, Gabriele Kociok-Köhn

Research output: Contribution to journalArticle

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Abstract

The present work deals with the synthesis of the 10-oxabicyclo[5.2.1]decane framework present in bioactive natural products like physalins, with potential as antitumor agents. This synthetic methodology involves several key reactions: (a) synthesis of polyfunctionalized cycloheptenones by [4 + 3] cycloaddition reactions of furan precursors with oxyallyl cations; (b) Nicholas reaction with propargyl cations stabilized as dicobalt hexacarbonyl complexes; (c) demetallation and hydration of the resulting acetylenes; (d) stereoconvergent aldol cyclization to generate a key oxatricyclic intermediate and (e) a β-fragmentation process that affords, under hypoiodite photolysis, the desired product with moderate to good yield. The final compounds are the result of a radicalary β-fragmentation at the level of C2-C6 with respect to the tertiary hydroxyl group on C6, with an unexpected contraction from a ten- to a nine-membered ring system, via a radical addition to the carbonyl group on C4. The synthetic methodology has been scaled up to multigram level with good overall yield. Further biological, biochemical and biophysical studies are being carried out in our laboratory on these 1,7-epoxycyclononane derivatives to determine the potential of this kind of oxabicyclic compound as future hits and/or leads for the development of new anticancer drugs. The preliminary evaluation of the anticancer activity of the representative synthesized compounds, against the leukaemia cancer cell lines K-562 and SR, shows a promising activity with a GI50 = 0.01 μM and a LC50 = 7.4 μM for a conveniently functionalized 10-oxabicyclo[5.2.1]decane.

Original languageEnglish
Pages (from-to)1557-1580
Number of pages24
JournalOrganic and Biomolecular Chemistry
Volume16
Issue number9
DOIs
Publication statusPublished - 7 Mar 2018

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activity (biology)
Biological Products
Cations
Alkynes
Cycloaddition
Photolysis
Cyclization
Cycloaddition Reaction
fragmentation
synthesis
products
Hydration
Hydroxyl Radical
Antineoplastic Agents
methodology
cations
Leukemia
leukemias
furans
Cells

ASJC Scopus subject areas

  • Biochemistry
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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Synthesis of the 10-oxabicyclo[5.2.1]decane framework present in bioactive natural products. / Montaña, Ángel M.; Ponzano, Stefano; Sanasi, Maria Filomena; Kociok-Köhn, Gabriele.

In: Organic and Biomolecular Chemistry, Vol. 16, No. 9, 07.03.2018, p. 1557-1580.

Research output: Contribution to journalArticle

Montaña, Ángel M. ; Ponzano, Stefano ; Sanasi, Maria Filomena ; Kociok-Köhn, Gabriele. / Synthesis of the 10-oxabicyclo[5.2.1]decane framework present in bioactive natural products. In: Organic and Biomolecular Chemistry. 2018 ; Vol. 16, No. 9. pp. 1557-1580.
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