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Preparation of 4′‐Spirocyclobutyl Nucleoside Analogues as Novel and Versatile Adenosine Scaffolds
Author(s) -
Verhoeven Jonas,
De Vleeschouwer Freija,
Kong Hanchu,
Van Hecke Kristof,
Pande Vineet,
Sun Weimei,
Vos Ann,
Wu Tongfei,
Meerpoel Lieven,
Thuring Jan Willem,
Verniest Guido
Publication year - 2019
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201904574
Subject(s) - furanose , nucleoside , chemistry , adenosine , cycloaddition , stereochemistry , combinatorial chemistry , nucleic acid , nucleotide , biochemistry , organic chemistry , ring (chemistry) , catalysis , gene
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.