Electrochemical Synthesis of Azanucleosides

Abstract

Recently, the nucleic acid medicine receiving a lot of attention because of various drug targets and few side effects compared with conventional low molecular medicine. The numerous nucleoside analogues have been reported. Especially, azanucleosides, in which the oxygen atom of furanose ring has been replaced with a nitrogen atom, show anticancer, antivirus, and antileukemia activity. Furthermore, azanucleosides exhibit tolerance towards nucleases when their incorporate into oligonucleotides. However, the traditional synthetic strategy requires multiple steps and harsh conditions, thereby limiting to obtain desired product with high yield. We developed mild condition and efficient synthesis of azanucleosides from prolinol derivative using by an electrochemical reaction in a 1.0 M lithium perchlorate-nitroethane and small amount of acetic acid mixture medium with a glassy carbon anode and platinum cathode. In this reaction, intermediate iminium cation was generated through anodic oxidation of N-α position. The nitroalkane solvent is suitable for cation-pool method because the cation intermediate species are stabilized at nearly room temperature. After 2.6 F of electricity, the nucleophiles were added into reaction medium and stirred overnight. We used each nucleobases (N6-benzoyl adenine: A(Bz), N4-benzoyl cytosine: C(Bz), N2-isobutyryl guanine: G(Ib)) as nucleophiles. The coupling with thymine (T) was carried out through silyl Hilbert-Johnson reaction from other prolinol derivative that has hydroxyl group in N-α position. It was also prepared by anodic oxidative C-H activation. As a result, desired deoxyribo-azanucleosides was obtained. However, the desired azanucleosides was generated as α and β anomer by equally ratio in this reaction. The natural nucleic acids are composed by only β-anomer nucleosides. In this reason, to regulate the anomeric selectivity is very important. Now, we are challenging the stereoselective synthesis of these deoxyribo-azanucleosides. Furthermore, we are applying our electrochemical method for the synthesis of ribo-azanucleosides.