Selective Synthesis of N6,3′,5′-Tripivaloyladenosine via Dynamic Kinetic Crystallization and Regioselective Preparation of Pivalated 2′-Deoxy-2′-fluoroarabinoadenosines

A four chemical step route to 2′-deoxy-2′-fluoro-N⁶,3′-dipivaloylarabinoadenosine and 2′-deoxy-2′-fluoro-N⁶-pivaloylarabinoadenosine from adenosine was developed for the preparation of ulevostinag in our STING (Stimulator of Interferon Genes) program. This 4-step route is based on the selective protection of adenosine with a dynamic kinetic crystallization of the desired N⁶,3′,5′-tripivaloyladenosine. This is followed by activation of the 2′-alcohol as its triflate without pivalate migration. Subsequently, the triflate is displaced with fluoride under mild conditions. Selective deprotection of the esters can give a variety of mono- and diacylated products including the 3′- or 5′-protected 2′-fluoroarabinonucleoside in the presence of the N⁶-pivalamide.