We report the synthesis of pyrene-conjugated azanucleoside-incorporated oligodeoxynucleotides (aza-ODNs). Combination of liquid-phase synthesis by alkyl-chain-soluble-support (ACSS) and electrochemical C–H activation realized efficient access to aza-ODNs without requiring an excess amount of reagent or solvent. The fluorescent properties of pyrene-conjugated aza-ODNs were also investigated. The resulting fluorescence spectrum indicated that the modification of the position of the nitrogen atom was suitable for the preparation of artificial functionalized oligonucleotides. A synthetic route to azaribose, as a precursor of aza-ODNs, was also reinvestigated to realize more efficient production. Electrochemical N-α-acetoxylation in 0.1 M lithium perchlorate/nitromethane/50 mM AcOH medium was found to be a suitable medium for this route. These results represent a new efficient synthetic route to aza-ODNs.

Azanucleosides, the sugar-modified nucleoside analogues, have various biological activities, while their efficient synthetic strategy is still under development. Herein, a novel method for the synthesis of pharmaceutically relevant azanucleosides, β-anomers of ribo-azanucleosides, by means of site-specific anodic C-H activation by using a nitroalkane-lithium perchlorate medium is reported. A mechanistic study of the electrochemical reaction and the armed/disarmed concept from traditional glycochemistry revealed that the 2'-substituent has a significant effect on the reactivity of prolinol derivative, and suitable carboxylic acid additives can control the reactivity of the intermediate species, an iminium cation equivalent. Finally, this method was demonstrated to be applicable for the synthesis of β-anomers of ribo-azanucleosides with all four nucleobases in a stereoselective manner.

Redox‐induced regioselective C(sp3)‐H C‐glycosidation for unactivated prolinols was achieved by controlling the anomeric reactivity of electrochemically generated iminium cations. A mechanistic study revealed that the intermediate was pooled as covalent azaribose or iminium cation species in situ, and the electrophilicity of intermediates can be adjusted by changing coexisting acids. We found that the armed/disarmed analogy concept of traditional glycochemistry can be adapted to our C‐glycosidation reaction. Finally, we invented a logical synthetic methodology, named “reactivity switching” concept, and synthesized a series of imino‐C‐nucleosides (C‐azanucleosides) based on this methodology.

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Azanucleosides in which the 4'-oxygen atom is replaced with a nitrogen atom are attracting considerable attention due to their anticancer and antiviral activities and resistance to nucleases. However, traditional synthesis strategies require multiple steps and harsh conditions, limiting the structural and functional diversity of the product. Reactive intermediates can be generated by directly activating target C-H bonds on the substrate by electro-organic reactions. We have also developed various electrochemical synthesis methods. Here, we report a novel synthesis method of pharmacologically relevant azanucleosides, riboazanucleosides via site-specific anodic C-H activation. The anodic oxidation reaction with a lithium perchlorate(LPC)–nitroethane medium activated N-acryloyl(Acr)-prolinol derivatives efficiently by decreasing the oxidation potential, possibly as a result of reduction of the Lewis acidity of Li+ by the nitroethane. When the activated prolinol substrate was coupled at the 5-position with nucleophiles, including nucleobases, the N-Acr group remained intact. The functionality of the prepared N-Acr-azanucleosides was readily increased by chemical modifications. In addition, C-glycoside is also valuable analogue for naturally occurred O-, N-glycosides because of its stability in biological condition. Especially, C-azanucleoside was developed as transition-state analog of purine nucleoside phosphorylase (PNP), which showing therapeutic effect for leukemia. This gave incentive to establish efficient synthetic method for C-azanucleoside by anodic oxidation. As a result of examining many reaction conditions, a coupling reaction between electroauxiliary (4-methoxyphenylthio group)-tethered prolinol and non-protected 9-deazahypoxanthine was accomplished in the LPC–nitromthane medium (1.0 M). This method opens the way for the electrosynthesis of various C-azanucleoside. Figure 1