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Photoinduced copper-catalysed deracemization of alkyl halides

Nature volume 640, pages 107–113 (2025)Cite this article

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Abstract

Deracemization is an emerging strategy for generating enantioenriched compounds wherein the two enantiomers of a readily available racemic starting material are transformed into a single enantiomer, typically through the action of a light-induced catalyst1,2. Excellent proof of principle for this potentially powerful approach to asymmetric catalysis has been described3,4,5,6,7,8; nevertheless, substantial challenges have not yet been addressed, including the exploitation of carbon–heteroatom (rather than only carbon–hydrogen and carbon–carbon) bond cleavage to achieve deracemization, as well as the development of processes that provide broad classes of useful enantioenriched compounds and tetrasubstituted stereocentres. Here we describe a straightforward method that addresses these challenges, using a chiral copper catalyst, generated in situ from commercially available components, to achieve the photoinduced deracemization of tertiary (and secondary) alkyl halides through carbon–halogen bond cleavage. Mechanistic studies (including the independent synthesis of postulated intermediates, photophysical, spectroscopic and reactivity studies, and density functional theory calculations) provide support for the key steps and intermediates in our proposed catalytic cycle, as well as insight into the origin of enantioselectivity.

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Fig. 1: Deracemization of stereogenic carbon centres.
Fig. 2: Photoinduced copper-catalysed deracemization of α,α-dialkyl-α-haloamides.
Fig. 3: Photoinduced copper-catalysed deracemization of other classes of electrophiles and synthetic utility.
Fig. 4: Mechanistic studies of photoinduced copper-catalysed deracemization.
Fig. 5: Investigation of the origin of enantioselectivity from DFT studies.

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Data availability

The data that support the findings of this study are available within the main text and its Supplementary Information, as well as from the Cambridge Crystallographic Data Centre (https://www.ccdc.cam.ac.uk/structures); crystallographic data are available free of charge under CCDC reference numbers 2285310, 2285314–2285317, 2285320, 2285322, 2285324, 2285325, 2368201, 2368202 and 2409546.

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Acknowledgements

This work has been supported by the National Institutes of Health (National Institute of General Medical Sciences, R35–GM145315 (G.C.F.) and R35–GM128779 (P.L.). We thank the Beckman Institute and the Dow Next-Generation Educator Fund for support and Takasago International Corporation for providing DTBM-SEGPHOS. We thank P. H. Oyala, M. K. Takase, D. Vander Velde, S. C. Virgil, J. R. Winkler (National Institutes of Health grant 1S10–OD032151), R. Anderson, H. Cho and Z.-Y. Wang for assistance and discussions. DFT calculations were carried out at the University of Pittsburgh Center for Research Computing and the Advanced Cyberinfrastructure Coordination Ecosystem: Services & Support (ACCESS) programme, supported by NSF award numbers OAC-2117681, OAC-1928147 and OAC-1928224.

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Author notes

  1. These authors contributed equally: Feng Zhong, Renhe Li

Authors and Affiliations

  1. Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, USA

    Feng Zhong, Renhe Li & Gregory C. Fu

  2. Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA

    Binh Khanh Mai & Peng Liu

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  1. Feng Zhong
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  2. Renhe Li
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  3. Binh Khanh Mai
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  4. Peng Liu
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Contributions

R.L. discovered and optimized the reaction. F.Z. and R.L. carried out the experiments illustrated in Figs. 2–4. B.K.M. performed the DFT calculations illustrated in Fig. 5. G.C.F. and P.L. directed the project. All authors contributed to the data analysis and the writing of the paper.

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Correspondence to Peng Liu or Gregory C. Fu.

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Zhong, F., Li, R., Mai, B.K. et al. Photoinduced copper-catalysed deracemization of alkyl halides. Nature 640, 107–113 (2025). https://doi.org/10.1038/s41586-025-08784-8

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