Journal
CHEMISTRY-A EUROPEAN JOURNAL
Volume 25, Issue 67, Pages 15419-15423Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.201904574
Keywords
cycloaddition; cyclobutanones; enol ethers; SAM-mimetics; spiro compounds
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Funding
- VLAIO
- Janssen Pharmaceutica NV [IWT140765]
- Vrije Universiteit Brussel
- FWO
- Hercules Foundation [AUGE/11/029]
- Special Research Fund (BOF)-UGent [01N03217]
- Flemish Supercomputer Centre (VSC)
- Free University of Brussels (VUB)
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Despite the large variety of modified nucleosides that have been reported, the preparation of constrained 4 '-spirocyclic adenosine analogues has received very little attention. We discovered that the [2+2]-cycloaddition of dichloroketene on readily available 4 '-exo-methylene furanose sugars efficiently results in the diastereoselective formation of novel 4 '-spirocyclobutanones. The reaction mechanism was investigated via density functional theory (DFT) and found to proceed either via a non-synchronous or stepwise reaction sequence, controlled by the stereochemistry at the 3 '-position of the sugar substrate. The obtained dichlorocyclobutanones were converted into nucleoside analogues, providing access to a novel class of chiral 4 '-spirocyclobutyl adenosine mimetics in eight steps from commercially available sugars. Assessment of the biological activity of designed 4 '-spirocyclic adenosine analogues identified potent inhibitors for protein methyltransferase target PRMT5.
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