Collect. Czech. Chem. Commun. 2010, 75, 1-20
Published online 2009-11-28 12:25:34

Synthesis of novel racemic carbocyclic nucleosides derived from 5,6-disubstituted norbornene

Michal Šálaa, Hubert Hřebabeckýa,*, Martin Dračínskýa, Milena Masojídkováa, Armando M. De Palmab, Johan Neytsb and Antonín Holýa

a Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i, Gilead Sciences and IOCB Research Center, 166 10 Prague 6, Czech Republic
b Rega Institute for Medical Research, Minderbroedersstraat 10, BE-3000, Leuven, Belgium


Novel class of the carbocyclic nucleosides based on bicyclo[2.2.1]heptene/heptane was prepared by two approaches. Thymine analogues were synthesized starting from methyl (1R*,4S*)-bicyclo[2.2.1]hepta-2,5-diene-2-carboxylate 1 by Michael addition of the thymine salt to the double bond as the key step. The yield and ratio of the isomers of this reaction depended on the used base (DBU, K2CO3). Purine nucleoside analogues were synthesized by the linear synthesis, the purine nucleobase was build-up on the amino group. The amino groups (exo/endo configuration) were introduced to the scaffold by the Curtius rearrangement. Norbornene analogues were converted to saturated and cis-hydroxylated nucleoside derivatives. [(1R*,2S*,3S*,4S*)-3-(6-Chloro-9H-purin-9-yl)bicyclo[2.2.1]hept-5-en-2-yl]methanol (13a) and [(1R*,2R*,3R*,4S*)-3-(6-chloro-9H-purin-9-yl)bicyclo[2.2.1]hept-5-en-2-yl]methanol (13b) showed moderate activity against Coxsackie virus CVB3.

Keywords: Carbanucleosides; Carbocyclic nucleosides; Nucleosides; Norbornenes; Purines; Coxsackie virus; Michael addition; Amino alcohols; Curtius rearrangement.

References: 38 live references.