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Enantioconvergent radical addition of racemic alkyl halides to access vicinal stereocentres

Nature Chemistry (2025)Cite this article

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Abstract

The development of synthetic methods that convert readily accessible chemicals into highly valuable small organic molecules, especially those with enantioenriched three-dimensional structures, holds substantial importance in organic synthesis. Alkyl halides are pivotal substrates for generating chiral C(sp3)–C(sp3) bonds. However, constructing modular vicinal stereogenic carbon centres from racemic alkyl halides, especially those bearing the sterically bulky quaternary carbon stereocentres frequently found in natural products, remains a daunting challenge. Here we report cobalt-catalysed enantioconvergent reductive addition of racemic alkyl halides with imines, allowing for efficient construction of various contiguous stereogenic centres, including tertiary–tertiary, tertiary–quaternary and quaternary–quaternary stereocentres with high diastereo- and enantioselectivities. The mild reaction conditions circumvent the use of organometallic reagents, ensuring broad functional group compatibility and enabling the formation of valuable chiral organic motifs such as amino acids, organophosphorus compounds, amino alcohols and γ-lactams. This reductive radical addition protocol also enables the stereoselective construction of C-glycosyl amino acids.

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Fig. 1: Overview of enantioconvergent reductive addition with racemic alkyl halides.
Fig. 2: Synthetic applications.

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Data availability

Crystallographic data for compounds 5, 33, 42, 78, 89, 98′, 102 and 124 are available from the Cambridge Crystallographic Data Center under reference numbers CCDC 2267486, 2339703, 2281055, 2347928, 2345237, 2348348, 2348347 and 2339794, respectively. All other data to support the conclusions are available in the main text or the supplementary materials.

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Acknowledgements

We thank the Analysis and Testing Center of East China University of Science and Technology for help with NMR and high-resolution mass spectrometry analysis. This work was supported by the National Natural Science Foundation of China (22171079, 22371071, 92356301, T2488302, 22471191, 2240011806), the Science and Technology Commission of Shanghai Municipality (grant number 24DX1400200), the Program of Introducing Talents of Discipline to Universities (B16017), the Scientific Committee of Shanghai (21JC1401700), the Shanghai Sailing Program (23YF1408800) and the Fundamental Research Funds for the Central Universities.

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Author notes

  1. These authors contributed equally: Xianqing Wu, Tingting Xia, Jiahao Bai, Yue Shi.

Authors and Affiliations

  1. Key Laboratory for Advanced Materials and Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, Frontiers Science Center for Materiobiology and Dynamic Chemistry, School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai, China

    Xianqing Wu, Tingting Xia, Jiahao Bai, Chengxu Fang, Jiangtao Hu, Wenwen Wu, Chenhuan Zhang, Qinglin Wang, Jingping Qu & Yifeng Chen

  2. Department of Chemistry, School of Science, Tianjin University, Tianjin, China

    Yue Shi & Genping Huang

  3. State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China

    Yifeng Chen

  4. School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, China

    Yifeng Chen

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  1. Xianqing Wu
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Contributions

Y.C. conceived of the project. X.W., T.X., J.B., C.F., J.H., W.W., C.Z. and Q.W. performed the experiments under the supervision of J.Q. and Y.C. Y.S. performed DFT calculations under the supervision of G.H. X.W., G.H. and Y.C. wrote the paper with feedback from all the other authors.

Corresponding authors

Correspondence to Genping Huang or Yifeng Chen.

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Extended data

Extended Data Fig. 1 Experimental mechanistic studies.

a, Radical clock experiment. b, Tracking the enantiopurity of the secondary α-chloroamides. c, Stereodivergent synthesis of 3. Standard condition: 1a (1.0 equiv.), 2 (1.5 equiv.), CoI2 (5 mol%), L4 (6 mol%), In (2.0 equiv.), EtOH (1.0 equiv.) in MeCN/THF (v/v = 1/1, 0.2 M) under 35 °C for 48 h. Isolated yields were reported, the e.e. was determined by chiral HPLC analysis and d.r. was determined by crude NMR.

Extended Data Fig. 2 DFT Calculations and proposed catalytic cycle.

a, C-Cl bond cleavage using IM1triplet as the active catalyst species. b, C-Cl bond cleavage and C-C bond formation using IM3d°ublet as the active catalyst species. c, Proposed catalytic cycle. The Gibbs free energies were computed at the level of (u)ωB97X-D4(SMD)/ZORA-def2-TZVPP//(u)BP86(SMD)/6-31 G(d)&SDD. R and S denote the stereochemical configuration of the product.

Extended Data Fig. 3 Origins of Stereoselectivity.

a, Optimized geometries and non-covalent interaction analysis of radical addition transition states. b, Structural analysis of IM1triplet. c, Distortion/interaction analysis of radical addition transition states. ΔE‡int: interaction energy, ΔE‡dist[2a’]: distortion energy of 2a’, ΔE‡dist[IM1triplet]: distortion energy of IM1triplet.

Supplementary information

Supplementary Information

Supplementary Figs. 1–24 and Tables 1–8.

Supplementary Data 1

Cartesian coordinates.

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Wu, X., Xia, T., Bai, J. et al. Enantioconvergent radical addition of racemic alkyl halides to access vicinal stereocentres. Nat. Chem. (2025). https://doi.org/10.1038/s41557-025-01967-w

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