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Stereoretentive radical cross-coupling

Nature volume 642, pages 85–91 (2025)Cite this article

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Abstract

Free radicals were first discovered more than 120 years ago by Gomberg1 and the first radical cross-couplings demonstrated by Kochi in the 1970s (ref. 2). In contrast to widely used polar cross-coupling chemistry to forge C(sp2)–C(sp2) bonds (such as Suzuki, Negishi and Kumada), radical cross-coupling is advantageous when applied to the coupling of saturated systems because of the mild conditions used and enhanced chemoselectivity associated with single-electron chemistry. The ability to use ubiquitous carbon-based fragments (such as carboxylic acids, alcohols, amines and olefins) in cross-coupling has greatly simplified access to various complex molecules3,4,5,6,7,8,9. Apart from these advantages, enantiospecific coupling reactions involving free radicals are unknown and generally believed to be challenging because of their near-instantaneous racemization (picosecond timescale)10. As a result, controlling the stereochemical outcome of radical cross-coupling can be achieved only on a case-by-case basis using bespoke chiral ligands11 or in a diastereoselective fashion guided by nearby stereocentres12. Here we show how readily accessible enantioenriched sulfonylhydrazides and low loadings of an inexpensive achiral Ni catalyst can be used to solve this challenge, thereby enabling enantiospecific, stereoretentive radical cross-coupling between enantioenriched alkyl fragments and (hetero)aryl halides without exogenous redox chemistry or chiral ligands. Calculations support the intermediacy of a unique Ni-bound diazene-containing transition state with C–C bond formation driven by loss of N2.

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Fig. 1: Enantiospecific radical cross-coupling.
Fig. 2: Reaction development and generality.
Fig. 3: Stereoretentive radical cross-coupling: simplifying synthesis, diastereocontrol and scalability.
Fig. 4: Proposed reaction pathways and associated mechanistic analysis.

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Data availability

All the data are available within the main text or the Supplementary Information. Experimental and characterization data for all new compounds prepared during this study are provided in the Supplementary Information. The X-ray crystallographic coordinate for Ni(4-Cl-bpy)(NO3)2·2H2O and compound 13-Ts has been deposited at the Cambridge Crystallographic Data Centre (CCDC) with accession codes 2425076 and 2411035, respectively. Copies of the data can be obtained free of charge at https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

This project is financially supported by NIH (GM-118176, P.S.B.) and the Gates Foundation (INV-056603, P.S.B. and Y.K.). L.M. thanks the Swedish Research Council (Vetenskapsrådet, VR-2023-00499) for a postdoctoral fellowship. F.C.A. acknowledges the ARC Centre of Excellence for Innovation in Peptide and Protein Science for Capacity Building (grant CBG117). We also thank D.-H. Huang and L. Pasternack (Scripps Research) for NMR spectroscopic assistance; M. Gembicky (UCSD) for X-ray analysis; and B. Orzolek, B. Sanchez and Q. N. Wong (Scripps Automated Synthesis Facility). We thank B. Jiang, M. Costantini and Á. Péter for their discussions. The computations presented here were conducted in the Garibaldi High Performance Computing (HPC) cluster, a facility supported by Scripps Research, La Jolla.

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  1. These authors contributed equally: Jiawei Sun, Jiayan He, Luca Massaro

Authors and Affiliations

  1. Department of Chemistry, Scripps Research, La Jolla, CA, USA

    Jiawei Sun, Jiayan He, Luca Massaro, David A. Cagan, Jet Tsien, Yu Wang, Flynn C. Attard, Yu Kawamata & Phil S. Baran

  2. Automated Synthesis Facility, Scripps Research, La Jolla, CA, USA

    Jillian E. Smith & Jason S. Lee

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Contributions

J.S., J.H., L.M., Y.K. and P.S.B. conceptualized the study. J.S., J.H., L.M., D.A.C., J.T., Y.W., F.C.A., J.E.S. and J.S.L. conducted the experimental investigation. J.S., J.H., L.M., D.A.C., J.T., Y.W., J.E.S., J.S.L., Y.K. and P.S.B. performed the data analysis. J.S., J.H., L.M., D.A.C., J.T., Y.K. and P.S.B. wrote the paper. Y.K. and P.S.B. helped with the fund acquisition. P.S.B. was in charge of the project administration.

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Correspondence to Phil S. Baran.

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Sun, J., He, J., Massaro, L. et al. Stereoretentive radical cross-coupling. Nature 642, 85–91 (2025). https://doi.org/10.1038/s41586-025-09011-0

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