Clarkson Rob, Komsta Zofia, Mayes Benjamin A, Moussa Adel, Shelbourne Montserrat, Stewart Alistair, Tyrrell Andrew J, Wallis Laura L, Weymouth-Wilson Alexander C
Dextra , Science and Technology Centre, Earley Gate, Whiteknights Road, Reading, RG6 6BZ, U.K.
J Org Chem. 2015 Feb 20;80(4):2198-215. doi: 10.1021/jo502712g. Epub 2015 Feb 4.
Construction of protected 2,3-dideoxy-2-fluoro-2,3-endo-methylene-pentofuranoses from d-glyceraldehyde and 2,3-dideoxy-2-fluoro-3-C-hydroxymethyl-2,3-endo-methylene-pentofuranoses from d-isoascorbic acid, via Simmons-Smith-type stereoselective cyclopropanations on the respective fluoroallyl alcohols, is described. Synthesis of the corresponding conformationally locked sugar modified uridine and guanosine nucleosides was achieved via Vorbrüggen or Mitsunobu methodologies. Stereochemical confirmation of the novel nucleosides was performed on the basis of 2D NOESY NMR experiments. Analysis of 2',3'-dideoxy-2'-fluoro-3'-C-hydroxymethyl-2',3'-endo-methylene-uridine by X-ray crystallography yielded the principal conformational parameters and indicated that the furanoid ring adopted an (o)E/(o)T1, East pucker. The uridine and guanosine nucleosides were found to be inactive in the hepatitis C virus (HCV) cell-based replicon assay, which was corroborated on examination of the corresponding nucleoside triphosphates against the HCV NS5B polymerase.
描述了通过在相应的氟代烯丙醇上进行Simmons-Smith型立体选择性环丙烷化反应，由d-甘油醛构建受保护的2,3-二脱氧-2-氟-2,3-内亚甲基戊呋喃糖，以及由d-异抗坏血酸构建2,3-二脱氧-2-氟-3-C-羟甲基-2,3-内亚甲基戊呋喃糖。通过Vorbrüggen或Mitsunobu方法实现了相应的构象锁定糖修饰的尿苷和鸟苷核苷的合成。基于二维NOESY NMR实验对新型核苷进行了立体化学确证。通过X射线晶体学分析2',3'-二脱氧-2'-氟-3'-C-羟甲基-2',3'-内亚甲基尿苷得到了主要的构象参数，并表明呋喃环采用了(o)E/(o)T1，东向扭曲构象。在丙型肝炎病毒(HCV)细胞复制子试验中发现尿苷和鸟苷核苷无活性，对相应的核苷三磷酸针对HCV NS5B聚合酶进行检测也证实了这一点。
