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

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• 作者：Roy K. Bowman ; Kae M. Bullock ; Royston C. B. Copley ; Nicole M. Deschamps ; Michael S. McClure ; Jeremiah D. Powers ; Andy M. Wolters ; Lianming Wu ; Shiping Xie
• 刊名：Journal of Organic Chemistry
• 出版年：2015
• 出版时间：October 2, 2015
• 年：2015
• 卷：80
• 期：19
• 页码：9610-9619
• 全文大小：571K
• ISSN：1520-6904

文摘

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