Convergent Synthesis of the NS5B Inhibitor GSK8175 Enabled by Transition Metal Catalysis

Abstract

A convergent eight-stage synthesis of the boron-containing NS5B inhibitor GSK8175 is described. The previous route involves 13 steps in a completely linear sequence, with an overall 10% yield. Key issues include a multiday S_NAr arylation of a secondary sulfonamide using HMPA as solvent, multiple functional group interconversions after all of the carbon atoms are installed (including a Sandmeyer halogenation), use of carcinogenic chloromethyl methyl ether to install a protecting group late in the synthesis, and an unreliable Pd-catalyzed Miyaura borylation as the penultimate step. We have devised an orthogonal approach using a Chan–Lam coupling between a halogenated aryl pinacol boronate ester and an aryl methanesulfonamide. This reaction is performed using a cationic Cu(I) precatalyst, which can be easily generated in situ using KPF₆ as a halide abstractor. High-throughput screening revealed a new Pd catalyst system to effect the penultimate borylation chemistry using simple monodentate phosphine ligands, with PCyPh₂ identified as optimal. Reaction progress analysis of this borylation indicated likely mass-transfer rate limitations under standard conditions using KOAc as the base. We have devised a K₂CO₃/pivalic acid system as an alternative, which dramatically outperforms the standard conditions. This new synthesis proceeds in eight stages with a 20% overall yield.