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

Abstract

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-carboxylate1by 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/endoconfiguration) were introduced to the scaffold by the Curtius rearrangement. Norbornene analogues were converted to saturated andcis-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 againstCoxsackievirus CVB3.