Synthesis Of Chiral Cyclopropyl Carbocyclic Pyrimidine Nucleosides Via Rhodium-catalyzed Asymmetric Cyclopropanations

In the continuous development of drug molecules,nucleoside drugs have demonstrated outstanding anti-tumor and antiviral activity,which has stimulated the research interests of researchers.However,the synthesis methods of traditional nucleoside drugs are complicated and extremely low yield,and the method for the synthesis of nucleoside and its analogues is very limited.Especially in the synthesis of chiral nucleoside analogues is rarely reported.In the known nucleoside drugs and their analogues,chiral cyclopropyl carbocyclic nucleoside analogues occupy a considerable proportion.Therefore,it is of great significance to synthesize chiral cyclopropyl carbocyclic nucleoside compounds and their derivatives by simple and efficient methods.The cyclopropyl carbocyclic is an important part of drug molecules that have been reported to have anti-human cytomegalovirus.Therefore,the synthesis of new nucleoside compounds with chiral ternary carbon ring has broad application prospect.In this Dissertation,we have developed an efficient and convenient catalytic reaction system for the synthesis of chiral carbocyclic pyrimidine nucleosides.A series of chiral carbocyclic pyrimidine nucleoside analogues containing all-carbon quaternary stereocenters were synthesized via the asymmetric intermolecular cyclopropanation of N1-vinyl pyrimidines andα-aryl diazoesters.During the experiment,we carefully screened the rate of addition of diazoester,the reaction temperature and the amount of catalyst.Finally,with 2 mol%of chiral dirhodium（II）carboxylate complex as the catalyst,a variety of chiral carbocyclic cytosine or uracil nucleoside analogs were obtained in good yields（up to 96%yield）,high diastereoselectivity（>20:1 dr）,and excellent enantioselectivities（up to 99%ee）.In the further derivatization experiment of the obtained ternary carbocyclic nucleoside compound,we first conducted a deprotection experiment on the protecting group of the product,and then performed a reduction reaction on the compound,and all the ee values of the products were maintained.the structures of the newly synthesized compounds were completely correct by ¹H NMR,¹³C NMR,HRMS.The absolute configuration of the chiral carbocyclic cytosine nucleoside analogue was determined by the single crystal X-ray diffraction analysis.