The Synthesis Of C~8Modified Purine Nucleosides By The Direct C-H Bonds Functionalization With Grignard Reagents

Purine bases and nucleosides have broad applications in biological and pharmaceutical chemistry. Various modified nucleosides play important roles in the anti-virus, anti-tumor and anti-AIDS process. After the unremitting efforts of scientists, a growing number of nucleoside drugs have been developed for the treatment of disease. Although the nucleoside drugs has good application prospects, but these drugs are still restricted by some problems, such as high production cost, low efficacy, side effect and so on. Therefore, the development of efficient methods to construct purine nucleosides are still the majority challenges for the chemical and pharmaceutical scientists. Herein, based on the concept of "high efficiency to construct purine nucleosides", several methods were designed. We use these new methods to synthesis a series of purine nucleosides.In this paper, we studied the synthesis of C-substituted purine nucleoside analogues, including the synthesis of C8-aryl-substituted purine analogues and C8-alkyl-substituted purine compounds. To make the synthetic sequence efficient and rapid, we use direct C-H bond activation method to construct this kind of compounds. We use Grignard reagent as the coupling partner, and nickel as catalyst to instead of precious metals. Using this method we have prepared42C8aryl or alkyl-substituted nucleosides.We also studied the new method for synthesis of C6-substituted purine nucleosides. A green and efficient protocol for the synthesis of C6-functionalized purine nucleosides was described via the direct nucleophilic substitution reaction of6-chloropurine derivatives and mild nucleophiles like PhOH, PhSH, PhNH2under microwave irradiated conditions without solvent. Compare with the reported methods, our method use solvent-free condition, which avoids the use of toxic solvents, ease of manipulation and broad spectrum substrates. Moreover, we also studied the use of new type Suzuki-Miyaura reaction to synthesis of C6-aryl purine nucleosides. The traditional Suzuki-Miyaura reaction was performed by boronic acid, but we found that sodium tetraarylborate also can be used as coupling partner. Sodium tetraarylborate have better atom economy and good solubility in water, which allow the reaction to be conducted in neat water under mild reaction conditions.Their structures were confirmed by1H-NMR,13C-NMR, HRMS.We report that this opens an effective new way for modification at C6and C8of purine nucleosides, and these results have good academic significance and applications.