Synthesis Of4’-Spirocyclic Modified Nucleoside Via1,3-Dipolar Cycloaddition Reaction

Modified nucleosides, such as ETV, ddC, LdT, etc., are currently employedin the multi-drug protocols adopted in therapeutic treatment of Virus infections. A newline of research has been recently opened in this field, which considers thereplacement of the modified ribose with an isoxazolidine nucleus. Preliminary in vivotests have shown a promising biological activity for some of the members of this newfamily of potential antiviral drugs. The antiviral activity exhibited by nucleosideanalogues has been correlated to some extent to preferred conformations achieved bythe drug in the formation of the enzyme–inhibitor complex, which temporarilyinhibits the DNA strand proliferation.Unmodified nucleosides rings exist in eitherS-type or N-type conformations.The observation that reverse transcriptase is able todiscriminate between two conformationally locked nucleoside analogues hasprompted the exploitation of strategies aiming at locking the puckering of thefuranose ring into one of the two rotamers. Our original strategy for the formation ofisoxazolidinyl nucleosides is based on the1,3-dipolar cycloaddition of nitrile oxideson4′,5′-unsaturated nucleosides achievable by a straightforward procedure.And studythe applicability of the reaction, the regioselectivity and stereoselectivity for syntheticnatural spiroheterocyclic compounds provide a theoretical basis.In the second chapter,sarting from adenosine,the convertion from5′-hydroxygroup to5′-iodo group by substitution reaction, and then eliminate one molecule ofhydrogen iodide in1N CH3ONa/CH3OH solution to give4′,5′-unsaturatedadenosine,the solvent, temperature of the reaction, and post-processing conditionswere optimized.We then tried using benzaldehyde as the starting materials, andconverted it to the corresponding oxime, NCS chlorinated,generated chloro oximein the eliminate of a molecule of hydrogen chloride was prepared in situ benzonitrileoxide,1,3-Dipolar cycloaddition between4′,5′-unsaturated adenosine and benzonitrile oxide in alkaline condition to give the product of cyclization, and thereaction solvent, the amount of benzonitrile oxide, the amount of triethylamine,and other conditions were optimized. Then we used another six aromatic aldehydes asraw materials to obtain the corresponding product of cyclization, and by examiningthe reaction rule found that the electronic effects and the steric hindrance of thesubstituent group has little impact on the yield and the stereoselectivity of thereaction.In the third chapter， We tried using propionaldehyde as the starting materials,and converted it to the corresponding oxime. Then Chloramine-T as oxidant oxidationoxime ethyl nitrile oxide and4′,5′-unsaturated adenosine occurred1,3-dipolarcycloaddition reaction by One-Pot method.But found that the glycosidic bond ofadenosine was cleaved, attempting to change the solvent, concentration of reactants,temperature, etc. are still unable to solve the problem.We tried using propionaldehydeoxime and NCS reflux in methylene chloride, directly added the4′,5′-unsaturatedadenosine and triethylamine cyclization to give the product of cyclization, and thereaction solvent, the amount of ethylthenitrile oxide, the amount of triethylamine, andother conditions were optimized. Respectively, using propionaldehyde,n-butyraldehyde, isobutyraldehyde as starting materials, and converted them tothe corresponding chloro oxime, respectively added the4′,5′-unsaturated thymidine or4′,5′-unsaturated and triethylamine cyclization to give the product of cyclization, sixcyclization products were obtained.