Synthesis Of3’-Modified-4’-Spirothymidine And Exploration Of Synthesis Of Spirouridine From Uridine And Dipoles

Nucleosides are a key means of human to resist the disease Caused by viruses.Now the medical and biological research show that the ribose conformation of naturalnucleoside and its ramifications can be recognize by the polymerase only when theirconformations are preferential in their metabolic process, and generate efficient andspecific biological effect. It shows that it would be an optimum method to obtainnucleosides with antiviral activity and antiviral drug by modify the conformation ofnucleosides artificially by chemical process. According to this principle, we analyzethe structure-function relationship of the antiviral nucleoside drugs, and found that themodification of deficiency of3’-hydroxy, azide group on3’-position and2’,3’-dideoxy didehydro on nucleoside sugar ring are possibly made the compounds beantiviral. Furthermore, the locking on conformation of conformational constrainednucleosides could increase the enzymatic activity in vivo, so we hope to combine thesugar ring modification and conformational constrain in order to get better antiviralactivity nucleosides. And4’-spirouridine nucleosides are a class of very important andvaluable nucleosides that are found in recent years. However, the synthetic route istoo long and difficult; in addition, the species of product are hard to diversify.Because of this, the4’-spriouridine nucleosides are not researched widely. Accordingto the situation, we design to synthesis the4’-spriouridine-2’,3’-modified thymidineand new structure uridine and dipoles to contain structure-function relationship ofcommon nucleoside drugs to enrich the types of product. Based on the exsitingliteratures and the works of our research group, we dicide to use1,3-Ddipolarcycloaddition reaction to synthesis the4’-spirouridine conformational constrainednucleosides efficiently.Firstly we planed to cyclized after modification. Modify the3’-position bychange the hydroxyl into hydrogen or azide group at first. During the process, weconverted the reagents and method according to the SN2mechanism that reduced steps and promoted the productive rate successfully. When synthesizing the3’-azidegroup thymidine, we have tried several ways and achieved the compouned finally.After that, we eliminate the5’-hydroxyl into4’,5’-double bond-3’-modified thymidine,and it reacted with nitrile oxide by1,3-dipolar cycloaddition reaction at last and reachedour goals.In order to enrich the species of conformational constrained nucleosides, wedesigned to synthesis4’-spirouridine-2’,3’-dideoxy didehydro uridine and new type ofdipoles with a starting of bromine acetaldehyde diethyl acetal. We made the1,3-dipolarcycloaddition reaction happen between4’-spirouridine uridine and nitrile oxide or nitroneon the basis of the experience of our research group with a high stereoselectivity ofnitrone cyclization. After that, we take adventage of trimethyl orthoformate to form acyclic structure with2’,3’-hydroxyls, and then eliminate it into double bond. Whenexploring new type of dipoles, we used the mechanism of TFA to remove acetal, and getbromoacetaldehyde efficiently. Furthermore, we improve some methods to avoid manyside reactions successfully. At last, we tried the the1,3-dipolar cycloaddition reactionwith the new dipoles by the method that we had been in use.