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Enantioselective synthesis of atropisomeric indoles via iron-catalysed oxidative cross-coupling

Nature Chemistry volume 15, pages 357–365 (2023)Cite this article

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Abstract

Heterobiaryl compounds that exhibit axial chirality are of increasing value and interest across several fields, but direct oxidative methods for their enantioselective synthesis remain elusive. Here we disclose that an iron catalyst in the presence of a chiral PyBOX ligand and an oxidant enables direct coupling between naphthols and indoles to yield atropisomeric heterobiaryl compounds with high levels of enantioselectivity. The reaction exhibits remarkable chemoselectivity and exclusively yields cross-coupled products without competing homocoupling. Mechanistic investigations enable us to postulate that an indole radical is generated in the reaction but that this is probably an off-cycle event, and that the reaction proceeds through formation of a chiral Fe-bound naphthoxy radical that is trapped by a nucleophilic indole. We envision that this simple, cheap and sustainable catalytic manifold will facilitate access to a range of heterobiaryl compounds and enable their application across the fields of materials science, medicinal chemistry and catalysis.

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Fig. 1: Oxidative cross-coupling reactions.
Fig. 2: Chemoselective derivatizations of enantioenriched biaryl 3o.
Fig. 3: Mechanistic investigations and proposed catalytic cycle.

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Data availability

All of the data (experimental procedures and characterization data) supporting the findings of this study are available within the article and its Supplementary Information files. Crystallographic data for compound 8 have been deposited with the Cambridge Crystallographic Data Centre under deposition number CCDC 2090406. These data can be obtained free of charge from https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

The Engineering and Physical Sciences Research Council (EPSRC) has provided financial support for a postdoctoral fellowship (to X.L.; EP/R005826/1) and studentships (to R.R.S. and M.J.H.K.) via the Centre for Doctoral Training in Synthesis for Biology and Medicine (EP/L015838/1). The Centre for Advanced Electron Spin Resonance is supported by the EPSRC (EP/L011972/1 and EP/V036408/1) and Oxford University Press John Fell Fund (0007019). We are grateful to O. Smith for X-ray crystallographic analysis and D. Pappo (Ben-Gurion University) and M. O’Donnell (Vertex) for helpful discussions. A CC-BY licence is applied to the author accepted manuscript arising from this submission, in accordance with EPSRC’s open access conditions.

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Authors and Affiliations

  1. Chemistry Research Laboratory, University of Oxford, Oxford, UK

    Richard R. Surgenor, Xiangqian Liu, Morgan J. H. Keenlyside & Martin D. Smith

  2. Inorganic Chemistry Laboratory, University of Oxford, Oxford, UK

    William Myers

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Contributions

R.R.S., X.L., M.J.H.K. and M.D.S. conceived of and designed the study. R.R.S., X.L. and M.J.H.K. performed the synthetic experiments and analysed the data for all compounds. W.M. performed the electron spin resonance study. R.R.S., X.L., W.M. and M.D.S. co-wrote the paper.

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Correspondence to Martin D. Smith.

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Nature Chemistry thanks Feng Shi and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Tables 1–16 and Figs. 1–11, synthetic procedures and characterization data for all compounds, data for mechanistic investigation (EPR, mass spectrometry and radical trapping data), a summary of the X-ray data, and pictorial NMR spectra (1H and 13C) for all compounds.

Supplementary Data 1

Crystallographic data for compound 8 (CCDC reference 2090406).

Supplementary Data 2

Crystallographic data (structure factors) for compound 8 (CCDC reference 2090406).

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Surgenor, R.R., Liu, X., Keenlyside, M.J.H. et al. Enantioselective synthesis of atropisomeric indoles via iron-catalysed oxidative cross-coupling. Nat. Chem. 15, 357–365 (2023). https://doi.org/10.1038/s41557-022-01095-9

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