Synthesis Of C4’-spirocyclic Pyrimidine Nucleoside Via Cyclopropanation Of α-Clcycloalkanones

Nucleosides and their analogues have excellent bioactivities in the aspects of anti-tumor and anti-viral.A variety of nucleoside compounds have been used as clinical drugs,for example,Entecavir,Lamivudine and Adefovir dipivoxil are used as anti-viral drugs.5-fluorouracil,Fludarabine and Capecitabine are used as anti-tumor drugs.Nucleoside drugs play an important role in the market of anti-viral drugs and anti-tumor drugs,Therefore,the synthesis of nucleoside compounds will be of great significance to the development of anti-tumor drugs and anti-viral drugs.Most of the spirocyclic nucleosides belong to conformational restricted nucleosides,and their molecular conformation compositions are unique.Before the substrates combine with the enzyme,the conformations of the enzyme will first change according to the substrates,they will form an active complex.The substrates with single conformation will be more favorable to combine with the enzymes.Therefore,the development of conformational restriction nucleoside drugs has advantages over non-conformation-restricted nucleoside drugs.Spirocyclic nucleosides are an important part of conformational restricted nucleosides,there are fewer reports about the synthesis methods of spirocyclic nucleosides.It is important to find a simple and efficient method of synthesizing spirocyclic nucleosides.Based on our team’s previous experience in synthesizing cyclic nucleoside,in this dissertation,α-pyrimidine-substituted propiolates are used as Michael acceptors.α-halocycloketones are used as nucleophilic reagents.In the presence of base,a cyclopropanation reaction was initiated by Michael addition,we get the spirocyclic nucleosides.Through careful screening of base,solvents,temperature and other conditions,we obtained a series of C4’-spirocyclic pyrimidine nucleosides.The most excellent yield is 85%.In this dissertation,nearly 30 pyrimidine nucleosides with spiro ring structure were synthesized based on the cyclopropanation of α-halocycloketones.We carried out structural characterization and conformation confirmation of the product by means of nuclear magnetic and single crystal diffractometers.It provides a new synthetic strategy for the synthesis of spirocyclic nucleosides and also provides an experimental basis for nucleoside libraries.It provides a new drug molecular entities and theory.It provides experimental support for searching for anti-tumor and anti0 viral drugs with high efficiency,low toxicity and less side effects.