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Synthesis of Nucleotides Bearing the 2′-O-Trifluoromethyl Group and Their Application in RNA Analogs Preparation

Xuan Chen,Long Xie,Chenglong Zhang,Shen Tian,Zeyu Tang,Ming Xiang,Weiwei Tian,Patrick Lu,Xianbin Yang

The integration of fluorine atoms into biologically active organic compounds has proved to be a vital technique in small molecule drugs. This technique can substantially enhance crucial properties, including metabolic stability, lipophilicity, and bioavailability, often with a mere addition of a single fluorine atom or a trifluoromethyl group. Over the past few decades, this concept has also been applied in nucleic acid chemistry. A commonly employed 2′-OH substitution is the introduction of a 2′-deoxy-2′-fluoro (2′-F) group. The strong electronegativity of fluorine prompts the modified siRNA to readily adopt a C3′- endo conformation, resulting in significant advantages in terms of binding affinity. To enrich the toolbox of chemical modification of oligonucleotides, the replacement of the 2′-OH with the 2′- O -trifluoromethyl group has been developed in RNA analog synthesis. Oligodeoxynucleotides containing the 2′- O -trifluoromethyl group can greatly increase the thermal stability of DNA/RNA duplexes depending on the position and amount of the modification. Moreover, 2′- O -trifluoromethylated oligodeoxynucleotide also exhibited a slightly higher resistance to snake venom phosphodiesterase than the unmodified oligodeoxynucleotide. The 2′- O -trifluoromethylated oligonucleotides can emerge as a label to study RNA structure and function as well, or to develop DNA/RNA-based diagnostics. Hence, it is necessary to report an effective method for the synthesis, deprotection, purification, and characterization of oligonucleotides bearing a 2′ -O -trifluoromethyl group. © 2024 Wiley Periodicals LLC. Basic Protocol 1 : Preparation of 6- N -benzoyl-5′- O -dimethoxytrityl-2′- O -trifluoromethyl adenosine 3′-(2-cyanoethyl N,N -diisopropyl)phosphoramidite Basic Protocol 2 : Preparation of 4- N -acetyl-5′- O -dimethoxytrityl-2′- O -trifluoromethyl cytidine 3′-(2-cyanoethyl N,N -diisopropyl)phosphoramidite Basic Protocol 3 : Preparation of 2- N -isobutyryl-5′- O -dimethoxytrityl-2′- O -trifluoromethyl guanine 3′-(2-cyanoethyl N,N -diisopropyl)phosphoramidite Basic Protocol 4 : Preparation of 5′- O -dimethoxytrityl-2′- O -2-trifluoromethyl uridine 3′-(2-cyanoethyl N,N -diisopropyl) phosphoramidite Basic Protocol 5 : Solid-phase synthesis of 2′- O -trifluoromethylated RNA analogs Basic Protocol 6 : Deprotection and purification of 2′- O -trifluoromethyl-RNAs