Ulevostinag (MK-1454) is a potent cyclic dinucleotide stimulator of interferon genes (STING) that was selected as a clinical candidate for evaluation in multiple solid tumor types. Nucleoside analogue 3′-deoxy-3′-α-fluroguanosine (3′FG) is one of two key monomeric subunits comprising Ulevostinag, and its efficient preparation was set as a key deliverable in the development of this novel therapeutic. We recently reported a novel synthetic approach to 3′FG, involving the aminocatalytic electrophilic fluorination and subsequent substrate-directed reduction of an isolable 2′-keto-nucleoside (i-Bu-3). Herein, we describe the process development of these key stereodefining steps, enabling the kilogram-scale preparation of i-Bu-3′FG (1). Key features of this process include (1) identification of commercially available l-leucine amide as an excellent fluorination catalyst, (2) development of a highly stereoselective (>95:5) intramolecular hydride delivery from the hindered nucleoside β-face, and (3) use of dispersive Raman spectroscopy to guide form control during the crystallization of 1.

中文翻译：

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关键 Ulevostinag 亚基的千克级合成的发展第二部分：氟化核苷的亲电方法

Ulevostinag (MK-1454) 是一种有效的干扰素基因 (STING) 环状二核苷酸刺激剂，被选为多种实体瘤类型的临床候选药物。核苷类似物 3'-deoxy-3'-α-fluoroguanosine (3'FG) 是构成 Ulevostinag 的两个关键单体亚基之一，其高效制备被设定为开发这种新型疗法的关键成果。我们最近报道了一种新的 3'FG 合成方法，涉及氨基催化亲电氟化和随后的底物定向还原可分离的 2'-酮-核苷 ( i -Bu-3 )。在此，我们描述了这些关键立体定义步骤的过程开发，使i -Bu-3'FG的公斤级制备成为可能( 1). 该过程的主要特征包括 (1) 将市售l-亮氨酸酰胺鉴定为优异的氟化催化剂，(2) 从受阻核苷 β-面开发高度立体选择性 (>95:5) 的分子内氢化物递送，以及 ( 3) 使用色散拉曼光谱来指导1结晶过程中的形态控制。