Abstract
The development of bimolecular homolytic substitution (SH2) catalysis has expanded cross-coupling chemistries by enabling the selective combination of any primary radical with any secondary or tertiary radical through a radical sorting mechanism1,2,3,4,5,6,7,8. Biomimetic9,10 SH2 catalysis can be used to merge common feedstock chemicals—such as alcohols, acids and halides—in various permutations for the construction of a single C(sp3)–C(sp3) bond. The ability to sort these two distinct radicals across commercially available alkenes in a three-component manner would enable the simultaneous construction of two C(sp3)–C(sp3) bonds, greatly accelerating access to complex molecules and drug-like chemical space11. However, the simultaneous in situ formation of electrophilic and primary nucleophilic radicals in the presence of unactivated alkenes is problematic, typically leading to statistical radical recombination, hydrogen atom transfer, disproportionation and other deleterious pathways12,13. Here we report the use of bimolecular homolytic substitution catalysis to sort an electrophilic radical and a nucleophilic radical across an unactivated alkene. This reaction involves the in situ formation of three distinct radical species, which are then differentiated by size and electronics, allowing for regioselective formation of the desired dialkylated products. This work accelerates access to pharmaceutically relevant C(sp3)-rich molecules and defines a distinct mechanistic approach for alkene dialkylation.
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Acknowledgements
We thank N. W. Dow and C. A. Gould for helpful scientific discussion. We also thank R. Lambert for assistance in preparing this manuscript. Research reported in this work was supported by the National Institute of General Medical Sciences of the National Institutes of Health (Grant R35 GM134897-04) and kind gifts from Merck, Pfizer, Janssen, Bristol-Myers Squibb, Genentech and Genmab. J.Z.W. and W.L.L. acknowledge Princeton University, E. Taylor and the Taylor family for an Edward C. Taylor Fellowship. W.L.L. acknowledges the National Science Foundation for a predoctoral fellowship (Award DGE-2039656).
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J.Z.W., W.L.L. and D.W.C.M. designed the experiments. J.Z.W. and W.L.L. performed and analysed the experiments. J.Z.W., W.L.L. and D.W.C.M. prepared this manuscript.
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D.W.C.M. declares a competing financial interest with respect to the Penn PhD Integrated Photoreactor, which is used to irradiate reactions in this work. The other authors declare no competing interests.
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Wang, J.Z., Lyon, W.L. & MacMillan, D.W.C. Alkene dialkylation by triple radical sorting. Nature 628, 104–109 (2024). https://doi.org/10.1038/s41586-024-07165-x
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DOI: https://doi.org/10.1038/s41586-024-07165-x
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