Synthesis Of3’,4’-Bicylconucleosides And3’,5’-Bicylco-2’,3’-seconucleosides

Nucleoside analogues is an important inhibitor of the enzyme in the viralreplication process which stops viral replication and prevents the virus from infectingtarget cells. It has been showed that the conformation of the nucleoside drug play acrucial impact in this process. So when a nucleoside or a nucleotide binds to anenzyme or its pharmacological target, only one conformer would be expected to beidentified by enzymes and generating a biological effect. Thus the synthesis ofnucleoside with different conformation is an important method for people to find neweffective nucleoside class of antiviral and the studies of conformational restrictionsnucleoside and acyclic nucleoside has been valued by the people. Now the3′,4′-linkedfused nucleoside have been reported for many years which has been not attractedmore attention, as the3′,4′-linked fused nucleoside the acyclic nucleoside withtriazole unit have also rarely research. So we intend to synthesis the3′,4′-linked fusednucleoside via1,3-dipolar cycloaddition with3′,4′-unsaturated nucleosides and nitrileoxides, and the acyclic nucleoside modified with triazole unit via Intramolecular1,3-dipolar cycloaddition between azide and alkynyl. The structure of the productwas characterized by1H NMR、¹³C NMR.In the first part of this paper, we synthesis the3′,4′-unsaturated uridine with naturaluridine as raw material by the reaction of oxidation, elimination and reduction, andthe corresponding oxime prepared from aldehyde was transformed into chloro oximewith NCS. Then we successfully synthesized the3′,4′-linked fused nucleoside via the1,3-dipolar cycloaddition between3′,4′-unsaturated uridine and nitrile oxides whichwere generated in situ with chloro oxime by elimination under Et₃N condition. Afterthat the cycloaddition reaction conditions were optimized. And in order to study thereaction scope, we changed the substituent（s） and its position at benzene ring of thenitrile oxides. A variety of3′,4′-linked fused uridines were synthesized. We found that no significant effect on the reaction and its selectivity by the electronic effect andsteric of the substituent. We got the corresponding cytidine product through theconversion of nucleotides which proved that the isoxazole in the3′,4′-linked fuseduridines were stable under the transformation condition. After this, we also studied thecycloaddition reaction beteeen tert-butyl3′,4′-unsaturated-5′-carboxylate uridine andnitrile oxides, a variety of cycloaddition products （which its isomer was obtained）were gained also. And we found that the reactivity of the latter is better than theformer which may due to the electron withdrawing effect of the tert-butyl5′-carboxylate which lead to the power shortage enhancements of3′,4′-double bondin the uridine. In addition, we also noted that the presence of tert-butyl5′-carboxylatehave a greater impact on the reaction stereoselectivity of benzaldehyde whichcontaining a ortho substituent such as methoxy wtih the larger steric. The stereoscopicstructure of the two isomeric products were characterized by NOE.In the second part of this paper, we describe the synthesis of3′,5′-bicylco-2′,3′-seconucleosides with natural uridine as raw material. Firstly we need tosynthesis the3′,4′-O-Isopropylideneuridine, afterward the propargyl was introduced tothe O5′position, then removal of the ketal protecting group under acidic conditions.5′-O-propargyl-2′,3′-secouridine was got via open-loop with oxidation by NaIO₄andreduction by NaBH₄. We obtain the cyclization precursor compound after the azidowas introduced to the C3′position which was refluxed in the toluene to give thecycloaddition product. Through the conversion of nucleotides we obtain thecorresponding cytidine derivative. The structure of the cycloaddition product wascharacterized by¹H NMR、¹³C NMR.