Development of a Kilogram-Scale Synthesis of a Key Ulevostinag Subunit Part II: An Electrophilic Approach to Fluorinated Nucleosides

Abstract

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.