The elusive 8-fluoroadenosine: a simple non-enzymatic synthesis and characterization

Article abstract of DOI:10.1016/j.tet.2007.02.053

The only successful synthesis of 8-fluoroadenosine reported until now relied on an enzymatic removal of the acetate protecting groups using thermally resistant hydrolases. In the present communication we describe the first non-enzymatic synthesis of 8-fluoroadenosine. According to this, the C₈-fluorine atom was introduced in a halogen-exchange process performed at elevated temperature. The chief obstacle in the synthesis of 8-fluoroadenosine, the removal of the protecting groups in the presence of the labile C₈-F bond, was addressed by judicious choice of acid-labile protecting groups. Their deprotection in the presence of C₈-F is described. Using this newly developed procedure, significant quantities of 8-fluoroadenosine were synthesized and, for the first time, its physicochemical properties including pH-dependent stability, examined in detail. The intermediate generation of 8-fluoroadenosines as a tool to increase the reaction rates of nucleophilic substitutions was briefly examined and successfully demonstrated with the example of 8-cyanoadenosine. The presented procedure is applicable to the synthesis of various adenosine analogs with potential pharmacological significance.