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.

Strategies for the Synthesis of Fluorinated Nucleosides, Nucleotides and Oligonucleotides

“…Yan and co‐workers [70] in 2020, expanded the scope of fluorine modification of guanine base that could have applications into the development of fluorine‐based bio‐probes. Authors in this report, describe the synthesis of 3′,5′‐ O ‐bis( tert ‐butyldimethylsilyl)‐8‐fluoro‐ N ‐2‐isobutyryl‐2′‐deoxyguanosine 13 a from 3′,5′‐ O ‐bis( tert ‐butyldimethylsilyl)‐ N ‐2‐isobutyryl‐2′‐deoxyguanosine 13 using a similar protocol reported by Zajc and co‐workers, albeit in this case only 20 % yield was obtained.…”

Editorial: Special Issue “Molecules from Side Reactions”

“…In the ninth paper, the authors discovered that the 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. These results prompted the authors to explore an alternative N-protecting group and to modify the solid phase synthetic cycle conditions [10]. In the tenth paper, the authors focused on the synthesis of peptidyl nucleosides as antibacterial agents.…”