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. Single crystal X-ray
diffraction and NMR studies supported the intramolecular hydrogen
bond shown in enamine lactone 22. The hydrogen bond was
considered an enabler in the proposed pathway from ester 6 to enamine lactone 22 and its rearrangement to amide 19. GSK852A (1) 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 1. 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.