Synthesis Of3’-Azido-3’-Deoxy-4’-Spirothymidine And2’,3’-Didehydro-2’,3’-Dideoxy-4’-Spirothymidine

The diseases which are caused by virus infection harm people’s health seriously.The nucleoside antiviral drugs are the significant measures of treating these diseases.So far, half of the antiviral drugs are nucleoside drugs. The nucleoside antiviral drugslike AZT and d4T which are used clinically are good antiviral drugs. Their antiviralactivity is higher, but they still have severe toxic and side effects. They also havesome problems about drug tolerance. To receive nucleosides with higher drug effectand lower toxicity, a lot of research groups work at synthesis and modification of newnucleosides. The conformation constrained nucleoside is an important kind ofnucleoside derivatives. It can produce very high specific selectivity during theinteraction between the drug and bio-enzyme because of the relative stiffnessconformation. So the conformation constrained nucleoside is always the hot topic.4’-spironucleoside is a kind of conformation constrained nucleosides which hasoriginal structure and higher potential enzymatic activity. The synthesis of it isdifficult, so the methods for synthesizing it is limited. Among them,1,3-dipolarcycloaddition is very useful because of the facile raw material, the mild reactionconditions and easy to diversify. This project have synthesized a series of4’-spironucleosides (3’-azido-3’-deoxy-4’-spirothymidine and2’,3’-didehydro-2’,3’-dideoxy-4’-spirothymidine) which are derived from AZT and d4T.This project include two parts of experimental studies. The first part hasdiscussed about the synthesis and diversification of3’-azido-3’-deoxy-4’-spirothymidine. We have designed three paths. As the hugesteric hindrance of the4’-spirothymidine which is synthesized through1,3-dipolarcycloaddition, we haven’t recieved the target products by the first two paths. Only thelast path can finish the synthesis: Starting from the natural thymidine, we have synthesized3’-azido-4’,5’-unsaturated thymidine first by converting3’-hydroxy and4’,5’-eliminating. Then we have synthesized different oxime chlorides from differentaromatic aldehydes. At last, we have synthesized3’-azido-3’-deoxy-4’-spirothymidine through1,3-dipolar cycloaddition between3’-azido-4’,5’-unsaturated thymidine and nitrile oxides which are created whiletriethylamine existing. We also have synthesized a series of new sugar-modifiednucleoside analogues which have a huge effect for the synthesis of nucleosidederivatives in the future. We have characterized the structures of the products by1HNMR,13C NMR and mass spectrum.Part Ⅱ has discussed about the synthesis and diversification of2’,3’-didehydro-2’,3’-dideoxy-4’-spirothymidine. We also have tried three paths, thefirst two paths have the same problems as partⅠhas. Only through the third path canwe synthesize the target compounds: We start from the natural thymidine and modifythe sugar ring to get2’,3’-didehydro-4’,5’-unsaturated thymidine. Then we also havesynthesized different oxime chloros. At last, we have synthesized2’,3’-didehydro-2’,3’-dideoxy-4’-spirothymidine through1,3-dipolar cycloaddition between2’,3’-didehydro-4’,5’-unsaturated thymidine and nitrile oxides which are created whiletriethylamine existing.