Development of a Kilogram-Scale Synthesis of a Key Ulevostinag Subunit Part I: Accessing a Keto-Nucleoside Intermediate from Guanosine

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.