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

Hatice G. Yayla, Feng Peng, Ian K. Mangion, Mark McLaughlin, Louis Charles Campeau, Ian W. Davies, Daniel A. Dirocco, Robert R. Knowles

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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.

Original languageEnglish (US)
Pages (from-to)2066-2073
Number of pages8
JournalChemical Science
Volume7
Issue number3
DOIs
StatePublished - Mar 1 2016

All Science Journal Classification (ASJC) codes

  • Chemistry(all)

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    Yayla, H. G., Peng, F., Mangion, I. K., McLaughlin, M., Campeau, L. C., Davies, I. W., Dirocco, D. A., & Knowles, R. R. (2016). Discovery and mechanistic study of a photocatalytic indoline dehydrogenation for the synthesis of elbasvir. Chemical Science, 7(3), 2066-2073. https://doi.org/10.1039/c5sc03350k