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Issue 3, 2016
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Discovery and mechanistic study of a photocatalytic indoline dehydrogenation for the synthesis of elbasvir

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Abstract

Elbasvir is a potent NS5A antagonist for the treatment of chronic hepatitis C. A seemingly trivial indoline oxidation en route to the target compound was complicated by epimerization of a stereogenic hemiaminal center under most standard oxidation conditions. To address this issue, a novel visible light photoredox process for indoline oxidation was developed involving an iridium photosensitizer and environmentally-benign perester oxidant. The reaction was discovered through a high-throughput experimentation campaign and the optimized process was demonstrated on 100 g scale in flow to afford a key intermediate towards the target compound. A battery of kinetic, electrochemical, and spectroscopic studies of this process indicates a radical chain mechanism of dehydrogenation involving selective HAT from the substrate by an alkoxy radicals. Notably, isotope effects were used to validate the chain mechanism when quantum yield data proved ambiguous.

Graphical abstract: Discovery and mechanistic study of a photocatalytic indoline dehydrogenation for the synthesis of elbasvir

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The article was received on 05 Sep 2015, accepted on 27 Nov 2015 and first published on 07 Dec 2015


Article type: Edge Article
DOI: 10.1039/C5SC03350K
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Citation: Chem. Sci., 2016,7, 2066-2073
  • Open access: Creative Commons BY-NC license
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    Discovery and mechanistic study of a photocatalytic indoline dehydrogenation for the synthesis of elbasvir

    H. G. Yayla, F. Peng, I. K. Mangion, M. McLaughlin, L. Campeau, I. W. Davies, D. A. DiRocco and R. R. Knowles, Chem. Sci., 2016, 7, 2066
    DOI: 10.1039/C5SC03350K

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