Hepatitis C is a potentially life-threatening viral infection affecting ~2% of the population and leading to &gt;500,000 deaths per year from complications of the disease. Though there are several approved treatments for the condition, development of alternative ways to combat potential viral resistance to current medicines is imperative. One important class of HCV (Hepatitis C virus) therapeutics is the NS5B inhibitors which operate by blocking the RNA polymerase activity of the NS5B viral enzyme. Building on our previous published findings on a non-nucleoside analogue NS5B inhibitor based on a substituted benzofuran scaffold (GSK852A), we herein report a highly convergent synthesis of our new NS5B molecule GSK8175 enabled by transition metal catalysis and high-throughput experimentation (HTE). The novel approach includes a Chan-Lam coupling between a halogenated aryl pinacol boronate ester and an aryl methanesulfonamide, performed using a cationic Cu(I) precatalyst. HTE revealed a new Pd catalyst system to effect the penultimate borylation chemistry using simple monodentate phosphine ligands. Due to mass transfer limitations under standard conditions using KOAc as the base, we have devised a K<sub>2</sub>CO<sub>3</sub>/pivalic acid system as an alternative, which dramatically outperforms the standard conditions. The new synthesis of GSK8175 proceeds in eight stages with a 20% overall yield.

Convergent synthesis of the NS5B inhibitor GSK8175 enabled by transition metal catalysis

2019 Fall National Meeting

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