Synthesis Of4’-spironucleosictes Via [3+2] Cycloaddition Between Nitrile Oxides And4’,5’-Unsaturated Thymidine

Anitviral drugs derived from nucleoside have played an essential role in therapyagainst epidemical diseases caused by virus infection. It has been shown that theconfirmation of the nucleoside is a key factor in its recognition and interaction to thetarget biomolecules. Thus, conformationally constrained nucleosides, restricting theconformation of nucleosides by structural modification, is a useful way to improve theaffinity and selectivity of nucleosides in search for drug candidates.4′-spironucleosides are one type of such important conformationally constrainednucleosides that were much less explored due to the difficulty in synthesis. In thesemolecules, the spiro ring fixed the glycosyl torsion angle while no nonbonded stericsuperimposition of the void space below C4′and the possibility of freeradical-induced degradation by hydrogen atom abstraction at C4′are precluded by thesubstitution pattern. The very few reported syntheses in general have some of thefollowing disadvantages: long route, low yield and lack of steroselectivities. Toovercome the above problems, we intend to expand the application of1,3-dipolarcycloaddition and design a novel and divers synthetical method for4′-spironucleosides by cycloaddition between4′,5′-unsaturated nucleosides anddifferent nitrile oxides. Compared with other literature syntheses, this method willprovide a shorter synthetic route with easily available starting material, under milderreaction condition and in more diverse fashion. Therefore, it is significant to study thesynthesis scope, to optimize the reaction condition and to investigate thestereoselectivity in developing this method as a new and efficient means for theconstruction of4′-spironucleosides.In the second chapter, we report two attempted synthetic methods forcycloaddition of4′,5′-unsaturated nucleoside with aromatic nitrile oxides which weregenerated in situ by oxidation with NaClO or by chlorination with NCS followed byelimination under basic condition. Under the first condition, the experiement results disclosed that the glucosidic bond of nucleoside was cleaved in the presence ofNaClO, while under the second condition the cycloaddition carried out smoothly togive the desired spiro-products. Then we optimized the reaction condition bychanging the amount of nirtrile oxide, base and the reaction time and, found theoptimized condition with good yield and steroselectivity. By change the substituent(s)and its position at aromatic ring in the nitrile oxides, we synthesized a variety ofspironucleosides. From the result of these experiments, we found that the electroniceffect and steric hindrance of the substituent group has little impact on the yield andthe stereoselectivity of the reaction. On contrary, we proved that the steric hindranceof3′-position in nucleoside dominated the stereoselectivity of the cycloadditon, whichwas profoundly inhanced by introducing a bulky protecting group TBDMS on3′-position. Furthermore, we also synthsized4′,5′-unsaturated threothymidine, inwhich the hydroxyl at3′-position orients to the β-face of the deoxy ribose, andinvestigated its reaction with phenyl nitrile oxide. In this reaction, a singlecycloaddition product was produced and, was proved by NOE experiements in NMRthat the configuration of the product on4′-position in the formed spironucleoside wasopposite to that of the product formed from counterpart4′,5′-unsaturated thymidine.Therefore, it demonstrates that the steric hindrance on3′-position but not the one ofnucleobase is the determining factor for the outcome of the stereochemistry for thecycloaddition reaction. Finally, we performed a two-step transformation to convert thenucleobase uricil to cytosine and synthesized4′-spiro5-methyl2′-deoxy cytidinederivative, which demonstrates that the isoxazole in the spironucleosides were stableunder the transformation and is also of biological interests in discovery of newantiviral nucleosides.