Conversion of a Benzofuran Ester to an Amide through an Enamine Lactone Pathway: Synthesis of HCV Polymerase Inhibitor GSK852A.

HCV NS5B polymerase inhibitor GSK852A (1) was synthesized in only five steps from ethyl 4-fluorobenzoylacetate (3) in 46% overall yield. Key to the efficient route was the synthesis of the highly functionalized benzofuran core 15 from the β-keto ester in one pot and the efficient conversion of ester 6 to amide 19 via enamine lactone 22. Serendipitous events led to identification of the isolable enamine lactone intermediate 22.