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Stereoretentive radical-based alkyl-alkyl cross-coupling.

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Title: Stereoretentive radical-based alkyl-alkyl cross-coupling.
Authors: Wang, Yu (AUTHOR), Sun, Jiawei (AUTHOR), Li, Yin (AUTHOR), Cagan, David A. (AUTHOR), Ring, Oliver T. (AUTHOR), Zeng, Xin (AUTHOR), Tsien, Jet (AUTHOR), Massaro, Luca (AUTHOR), Smith, Jillian E. (AUTHOR), Orzolek, Brandon J. (AUTHOR), Collins, Michael R. (AUTHOR), Kawamata, Yu (AUTHOR), Baran, Phil S. (AUTHOR)
Source: Science. 6/4/2026, Vol. 392 Issue 6802, p1075-1081. 7p.
Subjects: Nickel catalysts, Coupling reactions (Chemistry), Hydrazine derivatives, Chirality, Radicals (Chemistry), Stereospecificity, Oxidation-reduction reaction, Carbon-carbon bonds
Abstract: The construction of stereogenic C(sp3)–C(sp3) bonds through cross-coupling remains a formidable challenge owing to competing β-hydride elimination and homocoupling as well as the poor inherent stereocontrol of radical pathways. In this work, we report a scalable stereoretentive radical-radical cross-coupling of two distinct, transient alkyl radicals, derived from enantioenriched sulfonylhydrazides and achiral primary and secondary alkyl halides, achieved without chiral ligands, directing groups, or exogenous redox agents. This substrate-controlled approach leverages a nickel-catalyzed, redox-neutral manifold, which enables precise kinetic matching of diazene-mediated radical generation and halogen atom transfer. The reaction produced enantiospecificities of 80 to 96% and synthetically useful yields (up to 90%) across diverse piperidine and pyrrolidine scaffolds while tolerating ethers, free amines, aryl halides, heterocycles, olefins, and other sensitive motifs. Mechanistic studies support caged radical rebound at nickel to preserve chirality, followed by nickel(I)-nickel(III)–mediated radical capture and reductive elimination. Editor's summary: Chemical bond-forming reactions fall into two categories: ionic mechanisms with electron pair intermediates and radical mechanisms with unpaired electrons. Generally, the radical intermediates have fluctuating configurations and so tend to deliver two mirror-image products. Wang et al. present a protocol for coupling two alkyl radicals in which the nickel catalyst captures one of them so rapidly that it retains the configuration of its precursor. Constructing a library of homochiral sulfonylhydrazide precursors thereby enables versatile radical coupling to enantioenriched products without chiral catalysts. —Jake S. Yeston [ABSTRACT FROM AUTHOR]
Copyright of Science is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Stereoretentive radical-based alkyl-alkyl cross-coupling.
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  Data: <searchLink fieldCode="AR" term="%22Wang%2C+Yu%22">Wang, Yu</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Sun%2C+Jiawei%22">Sun, Jiawei</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Li%2C+Yin%22">Li, Yin</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Cagan%2C+David+A%2E%22">Cagan, David A.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Ring%2C+Oliver+T%2E%22">Ring, Oliver T.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Zeng%2C+Xin%22">Zeng, Xin</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Tsien%2C+Jet%22">Tsien, Jet</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Massaro%2C+Luca%22">Massaro, Luca</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Smith%2C+Jillian+E%2E%22">Smith, Jillian E.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Orzolek%2C+Brandon+J%2E%22">Orzolek, Brandon J.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Collins%2C+Michael+R%2E%22">Collins, Michael R.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Kawamata%2C+Yu%22">Kawamata, Yu</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Baran%2C+Phil+S%2E%22">Baran, Phil S.</searchLink> (AUTHOR)
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  Data: <searchLink fieldCode="JN" term="%22Science%22">Science</searchLink>. 6/4/2026, Vol. 392 Issue 6802, p1075-1081. 7p.
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  Data: The construction of stereogenic C(sp3)–C(sp3) bonds through cross-coupling remains a formidable challenge owing to competing β-hydride elimination and homocoupling as well as the poor inherent stereocontrol of radical pathways. In this work, we report a scalable stereoretentive radical-radical cross-coupling of two distinct, transient alkyl radicals, derived from enantioenriched sulfonylhydrazides and achiral primary and secondary alkyl halides, achieved without chiral ligands, directing groups, or exogenous redox agents. This substrate-controlled approach leverages a nickel-catalyzed, redox-neutral manifold, which enables precise kinetic matching of diazene-mediated radical generation and halogen atom transfer. The reaction produced enantiospecificities of 80 to 96% and synthetically useful yields (up to 90%) across diverse piperidine and pyrrolidine scaffolds while tolerating ethers, free amines, aryl halides, heterocycles, olefins, and other sensitive motifs. Mechanistic studies support caged radical rebound at nickel to preserve chirality, followed by nickel(I)-nickel(III)–mediated radical capture and reductive elimination. Editor's summary: Chemical bond-forming reactions fall into two categories: ionic mechanisms with electron pair intermediates and radical mechanisms with unpaired electrons. Generally, the radical intermediates have fluctuating configurations and so tend to deliver two mirror-image products. Wang et al. present a protocol for coupling two alkyl radicals in which the nickel catalyst captures one of them so rapidly that it retains the configuration of its precursor. Constructing a library of homochiral sulfonylhydrazide precursors thereby enables versatile radical coupling to enantioenriched products without chiral catalysts. —Jake S. Yeston [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Science is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1126/science.aef6981
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      – Code: eng
        Text: English
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      Pagination:
        PageCount: 7
        StartPage: 1075
    Subjects:
      – SubjectFull: Nickel catalysts
        Type: general
      – SubjectFull: Coupling reactions (Chemistry)
        Type: general
      – SubjectFull: Hydrazine derivatives
        Type: general
      – SubjectFull: Chirality
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      – SubjectFull: Radicals (Chemistry)
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      – SubjectFull: Stereospecificity
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      – SubjectFull: Oxidation-reduction reaction
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      – SubjectFull: Carbon-carbon bonds
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              Text: 6/4/2026
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