Kilogram-Scale Synthesis of 2′‑C‑Methyl-arabino-Uridine from Uridine via Dynamic Selective Dipivaloylation

We report a practical 3′,5′-diprotection strategy suitable for the kilogram-scale preparation of 2′-C-methyl-arabino-uridine, a key intermediate in the synthesis of the HCV NS5B inhibitor uprifosbuvir. Starting from uridine, dipivaloylation afforded an ∼2:1 mixture of 3′,5′- and 2′,5′-dipivaloyluridine. Subjecting this mixture to TEMPO/bleach oxidation promoted a dynamic acylation migration–selective oxidation to afford the 2′-ketone in 65% yield. Alternatively, treatment with 1 equiv of BF3 etherate led to the crystallization-driven equilibration and precipitation of 3′,5′-dipivaloyluridine·BF3 complex in a >50:1 ratio. After salt break, this mixture was oxidized in the presence of TEMPO/AcOOH to afford the 2′-ketone in 90% yield. Subsequent α-facial-selective methylation with MeMgBr/MnCl2 afforded 3′,5′-dipivaloylated 2′-C-methyl-arabino-uridine 12. This three-step process was successfully demonstrated on a multikilogram scale to afford the key intermediate for the manufacture of uprifosbuvir.