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Preparation of 4'-Spirocyclobutyl Nucleoside Analogues as Novel and Versatile Adenosine Scaffolds. | LitMetric

Preparation of 4'-Spirocyclobutyl Nucleoside Analogues as Novel and Versatile Adenosine Scaffolds.

Chemistry

Research Group of Organic Chemistry (ORGC), Department of Chemistry and Department of Bio-engineering Sciences, Faculty of Science and Bio-engineering Sciences, Vrije Universiteit Brussel (VUB), Pleinlaan 2, 1050, Brussels, Belgium.

Published: December 2019

AI Article Synopsis

  • Despite various modified nucleosides being reported, constrained 4'-spirocyclic adenosine analogues have not been studied much.
  • A new method involving [2+2]-cycloaddition of dichloroketene on 4'-exo-methylene furanose sugars was found to create unique 4'-spirocyclobutanones with specific stereochemistry.
  • The resulting compounds were successfully converted into chiral 4'-spirocyclobutyl adenosine mimetics, which showed strong potential as inhibitors for the protein methyltransferase PRMT5.

Article Abstract

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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Source
http://dx.doi.org/10.1002/chem.201904574DOI Listing

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