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

Author(s): Yayla, Hatice G.; Peng, Feng; Mangion, Ian K.; McLaughlin, Mark; Campeau, Louis-Charles; et al

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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.
Publication Date: 7-Dec-2016
Electronic Publication Date: 2016
Citation: Yayla, Hatice G., Peng, Feng, Mangion, Ian K., McLaughlin, Mark, Campeau, Louis-Charles, Davies, Ian W., DiRocco, Daniel A., Knowles, Robert R. (2016). Discovery and mechanistic study of a photocatalytic indoline dehydrogenation for the synthesis of elbasvir. Chemical Science, 7 (3), 2066 - 2073. doi:10.1039/C5SC03350K
DOI: doi:10.1039/C5SC03350K
ISSN: 2041-6520
EISSN: 2041-6539
Pages: 7, 2066 - 2073
Type of Material: Journal Article
Journal/Proceeding Title: Chemical Science
Version: Final published version. This is an open access article.



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