Synthesis of branched sugar nucleosides based on epoxy structure in the sugar portion

用二甲基二氧环的丙酮溶液氧化不饱和糖核苷，首次分离出相应的1′，2′-和4′，5′-环氧化物，这使我们能够与有机铝和有机硅试剂进行这些环氧化物的反应。因此，揭示了1‘和4’支链核苷的新途径，并评价了由此合成的支链核苷的抗病毒活性。在这些核苷类似物中，4′-乙基司他夫定被发现比临床使用的母体化合物司他夫定具有更高的抗hiv活性。4′-乙基司他夫定的其他优点如下：1)该化合物比司他夫定的细胞毒性小得多；2)与司他夫定相比，该化合物不抑制线粒体DNA的合成；3)该化合物与拉米夫定、埃武他滨、二danosine和齐多夫定协同作用抗HIV； 4)该化合物被纯化的人胸腺嘧啶激酶1（TK-1）磷酸化。TK-1对该化合物的磷酸化效率是司他夫定的四倍。5)当五谷嘌呤被分解代谢酶胸苷磷酸化酶分解时，该化合物的分解水平无法检测。4′-乙基司他夫定的这些特性促使我们进行了进一步的研究，特别是在开发这种化合物作为HIV药物时需要进行大规模的制备。上述利用二甲基二氧环的合成方法不适用于此目的，因为无法制备四浓度的二甲基二氧环丙酮溶液。因此，我们决定在4'位置应用亲核取代。以4′，5′-不饱和胸腺嘧啶衍生物为原料，与四苯甲酸铅反应，制备了该反应的底物。得到的4′-苯甲酰氧基衍生物与乙基铝试剂反应，得到了具有所需立体化学的4′-乙基化产物，产率为62%。对这一反应的精确检验表明，在4'位上的氯化反应是乙基化的第一步。虽然实际的反应机理还有待进一步研究，产率也有待进一步提高，但值得一提的是，这种烷化反应并没有使产物具有相反的4′立体化学。本课题还进行了1)4′-乙基司他夫定的5′-醛衍生物的合成：该化合物用于制备氚标记化合物；2)4′-乙基司他夫定的构效关系。对于后者，用CH_2和硫代替呋喃糖氧分别合成了类似物作为外消旋体。作为这些类似物的抗病毒评价结果，硫替代类似物被发现与司他夫定一样有效。目前正在对这种硫类似物进行光学分辨，以找出哪个对映体是真正的抗hiv活性化合物。少

Oxidation of unsaturated sugar nucleosides with an acetone solution of dimethyldioxirane allowed isolation of the corresponding 1',2'- and 4',5'-epoxides for the first time, This enabled us to carry out the reaction of these epoxides with organoaluminum and organosilicon regants. As a result, a new access to 1'-and 4'-branched nucleosides has been disclosed The branched nucleosides thus synthesized were evaluated their antiviral activity.Among these nucleoside analogues, 4'-ethynylstavudine was found to show higher anti-HIV activity than the parent compound stavudine which is under clinical use. Additional appeals of 4'-ethynylstavudine are listed below:1) This compound is much less cytotoxic than stavudine,2) to contrast to stavudine, this compound does not inhibit mitochondrial DNA synthesis,3) This compound acts synergistically with lamivudine, elvucitabine, didanosine, and zidovudine against HIV,4) This compound is phosphorylated by purified human thymidine kinase 1(TK-1) from CEM … More cells with a faster relative V_<mm> and a lower K_m value than stavudine, and efficiency of TK-1 in the phosphorylation of this compound is fourfold better than stavudine.5) While stave dine is broken down by the catabolic enzyme thymidine phosphorylase, the level of breakdown of this compound is below detection.These characteristics of 4'-ethynylstavudine led us to carry out further investigation, especially its large scale preparation that is necessary when developing this compound as an HIV agent. The above synthetic method utilizing dimethyldioxirane is not suitable for this purpose, because a 4 concentrated acetone solution of dimethyldioxirane cannot be prepared. We, therefore, decided to apply nucleophilic substitution at the 4'-position. The substrate for this reaction was prepared again from 4',5'-unsaturated thymine derivative by reacting with lead tetrabenzoate. The resulting 4'-benzoyloxy derivative, upon reacting with an ethynylaluminum reagent, gave the 4'-ethynylated product with the desired stereochemistry in 62% yield. Precise examination of this reaction revealed that chlorination at the 4'-position is the initial step for the ethynylation. Although actual reaction mechanism remains to be investigated and also the yield has to be improve, it is to be mentioned that this ethnylation gave none of the product having opposite 4'-stereochemstry.Other studies carried out in this project are 1) the synthesis of 5'-aldehyde derivative of 4'-ethynylstavudine : this compound is to be used for the preparation oftritium labeled compound, 2) structure-activity relationships of 4'-ethynylstavudine. For the latter purpose, analogues with CH_2 and sulfur instead of furanose oxygen were synthesized each as a racemate. As a result of antiviral evaluation of these analogues, the sulfur-replaced analogue was found to be as active as stavudine. Optical resolution of this sulfur analogue is now under way to find out which enantiomer is actual anti-HIV active compound. Less