Diastereoselective Synthesis of C2′-Fluorinated Nucleoside Analogues Using an Acyclic Approach

Nucleoside analogues bearing a fluorine in the C2′-position have been synthesized by SN2-like cyclizations of acyclic thioaminal precursors. This strategy provides access to two scaffolds, d-1′,2′-cis-thiofuranosides and d-1′,2′-trans-furanosides, which are difficult to generate using the standard approach for nucleoside synthesis. The addition of silylated nucleobases onto model C2-fluorinated dithioacetal substrates resulted in 1,2-syn diastereoselectivity, which is consistent with the C2–F and S-alkyl moiety being in close proximity. A new series of analogues bearing a C3′ all-carbon quaternary center along with a C2′–F atom have also been synthesized using this approach and are being investigated as potential antimetabolites.通过对无环硫代缩醛胺前体进行类SN2环化反应，成功合成了C2′位带有氟原子的核苷类似物（Nucleoside analogues）。该策略可获得两类难以通过常规核苷合成方法制备的骨架：d-1′,2′-顺式硫呋喃糖苷与d-1′,2′-反式呋喃糖苷。将硅基化核苷碱基引入模型C2-氟代二硫缩醛底物后，反应呈现1,2-顺式非对映选择性，这与C2-F键与S-烷基基团处于近距离空间位置的特征相符。本研究还通过该方法合成了一系列同时带有C3′全碳季碳中心与C2′-F原子的新型核苷类似物，目前正将其作为潜在抗代谢物开展相关研究。