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

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.

SUBMITTER: Yayla HG

PROVIDER: S-EPMC5968518 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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

Yayla Hatice G HG Peng Feng F Mangion Ian K IK McLaughlin Mark M Campeau Louis-Charles LC Davies Ian W IW DiRocco Daniel A DA Knowles Robert R RR

Chemical science 20151207 3

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 exp ...[more]

PMID: 29899932

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Project description:Solid/liquid heterogeneous photocatalysis was often considered to occur on the active sites of a solid catalyst surface. Herein, we report that the selectivity of photocatalytic dehydrogenative oxidations of aliphatic primary alcohols in acetonitrile solution into corresponding aldehydes exhibits an anomalous relationship with adsorption behavior of the alcohols. By using Pt-loaded TiO2 photocatalyst in an inert atmosphere under UV light illumination, primary short-chain alcohols (SCAs) with strong adsorption were dehydrogenated into aldehydes in very poor selectivity, whereas weak-adsorbable long-chain alcohols (LCAs) were transformed into corresponding aldehydes with much higher selectivity. More than 20 examples of primary LCAs (C4-C10) were successfully transformed into their corresponding aldehydes with satisfactory selectivity and yield. Both solid-state magic-angle-spinning 13C NMR and attenuated total reflectance-Fourier transform infrared spectroscopy studies provided concrete differences in adsorption behaviors on the Pt-TiO2 photocatalyst surface between SCA ethanol and LCA n-octanol. To further uncover the mechanism for different selectivities of SCAs and LCAs in photodehydrogenation, in situ electron paramagnetic resonance (EPR) experiments (at 8 K temperature) were employed to observe the oxidation features of photogenerated hole in the valance band of Pt-TiO2 (hvb +). The EPR experimental studies exhibited that unlike ethanol, either n-octanol or solvent acetonitrile alone all could not scavenge photogenerated hvb + on Pt-P25 photocatalyst and only n-octanol dissolved in acetonitrile solvent could smoothly react with photoinduced hole. This indicated that selective oxidations of LCAs were achieved by solvent-delivered oxidation rather than directly destructive oxidation of photogenerated hvb +. Our results may open an alternative way in selective dehydrogenative oxidation of various substrates sensitive to both dioxygen and high-temperature treatments.

Dataset Information

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

Publications

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

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