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

Abstract

HCV NS5B polymerase inhibitor GSK852A (<b>1</b>) was synthesized in only five steps from ethyl 4-fluorobenzoylacetate (<b>3</b>) in 46% overall yield. Key to the efficient route was the synthesis of the highly functionalized benzofuran core <b>15</b> from the β-keto ester in one pot and the efficient conversion of ester <b>6</b> to amide <b>19</b> via enamine lactone <b>22</b>. Serendipitous events led to identification of the isolable enamine lactone intermediate <b>22</b>. Single crystal X-ray diffraction and NMR studies supported the intramolecular hydrogen bond shown in enamine lactone <b>22</b>. The hydrogen bond was considered an enabler in the proposed pathway from ester <b>6</b> to enamine lactone <b>22</b> and its rearrangement to amide <b>19</b>. GSK852A (<b>1</b>) was obtained after reductive amination and mesylation with conditions amenable to the presence of the boronic acid moiety which was considered important for the desirable pharmacokinetics of <b>1</b>. The overall yield of 46% in five steps was a significant improvement to the previous synthesis from the same β-keto ester in 5% yield over 13 steps