A kilogram-scale synthesis of a key fragment of Ulevostinag (MK-1454), a cyclic dinucleotide agonist of the stimulator of interferon genes (STING), is described. Ulevostinag comprises two non-natural nucleoside derivatives linked together via two P-chiral phosphorothioate groups. The strategy utilized to prepare one of these nucleosides, namely, 3′-deoxy-3′-α-fluoro-guanosine (3′-FG), hinges on a diastereoselective α-fluorination of a key keto-nucleoside derivative, followed by substrate-directed reduction of the ketone. Herein, we describe the development of a robust and scalable synthesis of this intermediate, a 3′-deoxy-2′-keto-guanosine derivative, from guanosine. Salient features of the approach include activation of the 2′ and 3′-alcohol groups of guanosine as a bis-tosylate, which enables regioselective E2 elimination to simultaneously deoxygenate the 3′-position and generate the 2′-ketone.

中文翻译：

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关键 Ulevostinag 亚基的千克级合成的发展第 I 部分：从鸟苷中获取酮核苷中间体

描述了 Ulevostinag (MK-1454) 关键片段的千克级合成，Ulevostinag 是干扰素基因 (STING) 刺激物的环状二核苷酸激动剂。Ulevostinag 包含通过两个P连接在一起的两个非天然核苷衍生物-手性硫代磷酸酯基团。用于制备这些核苷之一的策略，即 3'-deoxy-3'-α-fluoro-guanosine (3'-FG)，取决于关键酮-核苷衍生物的非对映选择性 α-氟化，然后是底物-定向还原酮。在此，我们描述了这种中间体（一种来自鸟苷的 3'-脱氧-2'-酮-鸟苷衍生物）稳健且可扩展合成的开发。该方法的显着特征包括将鸟苷的 2' 和 3'-醇基激活为双甲苯磺酸盐，这使得区域选择性 E2 消除能够同时使 3'-位脱氧并产生 2'-酮。