Synthesis Of Acyclic Nucleosides With Chiral Amino Side Chain By Mitsunobu Reaction

Nowadays the main diseases which are intimidating the health of human are hepatitis, tumor and AIDS. The synthesis of medicines which are less harmful for human and more effective for the three diseases has always been the common target for many pharmacists. Nucleosides and their derivatives play important roles in antitumor, antivirus and anti-HIV drugs and are recognized as the indispensable and the most important antivirus drugs. The medicines used for these diseases have been extensively developed by now. Yet these medicines have some universal drawbacks such as weak performance, side effects and highcost. So the designing and synthesis of new medicines are still important task for pharmacists. Chiral acyclicnucleosides are compounds which played very important roles that are expected to have a potential biological impact especially toward anti-herpesvirus and anti-retrovirus activity. Herein, we reported a novel method for the synthesis of novel chiral acyclic nucleoside analogues through Mitsunobu reaction between purine or pyrimidine bases and N-trityl-L-serine methyl ester.Initially, we investigated the Mitsunobu reaction between 6-chloropurine and N-tert-butoxycarbonyl (Boc) L-serine methyl ester. And found that the primary product is not the expected Mitsunobu substituted product but the elimination product of N-tert-butoxycarbonyl (Boc) L-serine methyl ester. A survey of literature demonstrated that when Cbz or Boc was used as the N-protecting group for serine, the elimination product is in main along with a small amount of the nucleophilic substitution product. According to the literature, we decided on trityl (Tr) as the N-protecting group and methyl ester as the carboxyl-protecting group.And then, we performed the purine derivatives through Mitsunobu coupling reaction to obtain the chiral acyclicnucleoside. We optimized the reaction condition, and conducted the reaction in different solvents.Next,we applied this procedure to pyrimidine derivatives. To our delight, the target molecules could also obtained in moderate to good isolated yields.It is worth mentioning that these novel chiral acyclic nucleoside analogues can be used as key intermediates in the synthesis not only of naturally occurring (S)-willardiine and its analogues, but also of (S)-DHPA-like nucleoside analogues. Besides the chiral acyclonucleosides analogues we synthesizd are good monomers for the synthesis of PNA.Compared with previously known approaches, the simplicity of this procedure, the absence of toxic base and generally satisfactory yields make this method particularly attractive. This method suggests an opportunity to acquire many other useful derivatives from these chiral acyclic nucleosides.