8-Fluoro-N-2-isobutyryl-2′-deoxyguanosine: Synthesis and Reactivity

Abstract

3′,5′-O-Bis(tert-butyldimethylsilyl)-8-fluoro-N-2-isobutyryl-2′-deoxyguanosine was synthesized from 3′,5′-O-bis(tert-butyldimethylsilyl)-N-2-isobutyryl-2′-deoxyguanosine by the treatment with N-fluorobenzenesulfonimide. A similar fluorination reaction with 3′,5′-O-bis(tert-butyldimethylsilyl)-N-2-(N,N-dimethylformamidine)-2′-deoxyguanosine, however, failed to give the corresponding fluorinated product. It was found that 8-fluoro-N-2-isobutyryl-2′-deoxyguanosine is labile under acidic conditions, but sufficiently stable in dichloroacetic acid used in solid phase synthesis. Incorporation of 8-fluoro-N-2-isobutyryl-2′-deoxyguanosine into oligonucleotides through the phosphoramidite chemistry-based solid phase synthesis failed to give the desired products. Furthermore, treatment of 8-fluoro-N-2-isobutyryl-2′-deoxyguanosine with aqueous ammonium hydroxide did not give 8-fluoro-2′-deoxyguanosine, but led to the formation of a mixture consisting of 8-amino-N-2-isobutyryl-2′-deoxyguanosine and C8:5′-O-cyclo-2′-deoxyguanosine. Taken together, an alternative N-protecting group and possibly modified solid phase synthetic cycle conditions will be required for the incorporation of 8-fluoro-2′-deoxyguanosine into oligonucleotides through the phosphoramidite chemistry-based solid phase synthesis.