title: 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 (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.
authors.affiliation: Product Development, GlaxoSmithKline , 5 Moore Drive, Research Triangle Park, Durham, North Carolina 27709, United States.
authors.forename: Roy K
authors.initials: RK
authors.lastname: Bowman
authors.affiliation: Product Development, GlaxoSmithKline , 5 Moore Drive, Research Triangle Park, Durham, North Carolina 27709, United States.
authors.forename: Kae M
authors.initials: KM
authors.lastname: Bullock
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.
authors.forename: Royston C B
authors.initials: RC
authors.lastname: Copley
authors.affiliation: Product Development, GlaxoSmithKline , 5 Moore Drive, Research Triangle Park, Durham, North Carolina 27709, United States.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Deschamps
authors.affiliation: Product Development, GlaxoSmithKline , 5 Moore Drive, Research Triangle Park, Durham, North Carolina 27709, United States.
authors.forename: Michael S
authors.initials: MS
authors.lastname: McClure
authors.affiliation: Product Development, GlaxoSmithKline , 5 Moore Drive, Research Triangle Park, Durham, North Carolina 27709, United States.
authors.forename: Jeremiah D
authors.initials: JD
authors.lastname: Powers
authors.affiliation: Product Development, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Andy M
authors.initials: AM
authors.lastname: Wolters
authors.affiliation: Product Development, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Lianming
authors.initials: L
authors.lastname: Wu
authors.affiliation: Product Development, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Shiping
authors.initials: S
authors.lastname: Xie