Synthesis Of Chiral Carbocyclic Pyrimidine Nucleosides Via Asymmetric Cyclopropanation

nucleosides have displayed important antivirus activities with versatile applications in medicinal chemistry.nucleoside has shown antiviral activity against human immunodeficiency virus(HIV),hepatitis B virus(HBV),hepatitis C virus(HCV)and cytomegalovirus(CMV)and other viral diseases.Nucleoside is a novel antiviral medicine that has displayed an impressively excellent treatment effect that has never been seen before in antiviral activity.For the synthetic routes to chiral unnatural pyrimidine nucleosides,in addition to the derivatization of natural nucleosides,the main pathway is the glycosylation between chiral sugar rings and activated pyrimidine bases,which faces the challenge of controlling diastereoselectivity.Therefore,it is necessary to develop an efficient method for the synthesis of carbocyclic nucleosides.Synthesis of Chiral Cyclopropyl Carbocyclic Nucleosides via Asymmetric Intramolecular Cyclopropanations Catalyzed has poor reported.In this paper,the synthesis of chiral carbopyrimidine nucleosides by cyclopropanation of pyrimidine derivatives was studied.This paper is divided into two parts as follows:1.Synthesis of chiral carbopyrimidine nucleosides via asymmetric cyclopropane Catalytic with Phenyliodonium ylideInitially,the reaction between Bz-protected N1-vinylthymine and Phenyliodonium ylide was chosen as the model reaction.optimized reaction conditions,includes catalyst,chiral ligand and dosage,reaction temperature,time,solvent,additive,etc.Through a series of experiments,the best reaction conditions were obtained Cu(OTf)2 as catalyst,mixed solvent fluorobenzene: 1.3-dichlorobenzene = 1:2,4? MS molecular sieve as additive,and reacting in the atmosphere of-20 oC,nitrogen.Under optimized reaction conditions the chiral carbopyrimidine nucleosides with excellent yield(up to 98%)and excellent enantioselective(> 99%).1.Synthesis of chiral carbocyclic pyrimidine nucleosides via asymmetric cyclopropanationIn this paper,the cyclopropane reactions of α-Pyrimidine substituted acrylate and diethyl bromomalonate have been developed.Initially,α-Pyrimidine substituted acrylate was selected as a model electrophilic alkene to react with diethyl bromomalonate.The reaction conditions include temperature,solvent,catalyst and its dosage,alkali and its dosage,and additive.Through a series of experiments,the best reaction conditions were obtained using Cs2CO3 as the base in mixed solvent dichloromethane: acetonitrile = 2:1 at 0oC reaction 48 h,With quinine derivative(DHQD)2AQN as the organocatalyst.Under optimized reaction conditions the chiral carbopyrimidine nucleosides with excellent yield(up to 93%),excellent enantioselective(96%)and excellent diastereoselective(> 20:1).We found that the products with the amide bond blocking spin isomerization can be characterized by NMR.but this kind of products can not be separated,so there is no relevant research.But this phenomenon can be solved by high temperature NMR..At last,all the products were characterized by 1HNMR,13 CNMR and HPLC..The absolute configuration of the product was determined by X-ray.In this paper,the enantioselective synthesis of pyrimidine nucleosides by catalytic asymmetric cyclopropane was studied.A series of pyrimidine compounds were synthesized,and the new methods and ideas of structural modification of pyrimidine nucleosides were broadened.This research enriches the diversity of pyrimidine nucleosides and the nucleoside library,which provides convenience for medicine screening in the future.At the same time,the ternary carbopyrimidine nucleosides products are expected to have a good application prospect in new medicine research and development.