Abstract
Cytochrome P450 enzymes are known to catalyse bimodal oxidation of aliphatic acids via radical intermediates, which partition between pathways of hydroxylation and desaturation1,2. Developing analogous catalytic systems for remote C–H functionalization remains a significant challenge3,4,5. Here, we report the development of Cu(I)-catalysed bimodal dehydrogenation/lactonization reactions of synthetically common N-methoxyamides through radical abstractions of the γ-aliphatic C–H bonds. The feasibility of switching from dehydrogenation to lactonization is also demonstrated by altering reaction conditions. The use of a readily available amide as both radical precursor and internal oxidant allows for the development of redox-neutral C–H functionalization reactions with methanol as the sole side product. These C–H functionalization reactions using a Cu(I) catalyst with loading as low as 0.5 mol.% is applied to the diversification of a wide range of aliphatic acids including drug molecules and natural products. The exceptional compatibility of this catalytic system with a wide range of oxidatively sensitive functionality demonstrates the unique advantage of using a simple amide substrate as a mild internal oxidant.
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Data availability
Crystallographic data for compounds B63, B64, C27, C86, C101 and C102, as well as for derivatives of B62 (labelled as B62-ketone) and B65 (labelled as B65-Ac) are available in the Supplementary Information files and from the Cambridge Crystallographic Data Center under reference numbers CCDC 2279927, CCDC 2271734, CCDC 2271733, CCDC 2271730, CCDC 2271732, CCDC 2271731, CCDC 2296322and CCDC 2296327, respectively. All other data supporting the findings of this study are available in the Article and its Supplementary Information.
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Acknowledgements
We thank the Scripps Research Institute, National Institutes of Health (NIGMS, 2R01GM084019) for financial support. The content is solely our responsibility and does not necessarily represent the official views of the National Institutes of Health. We thank D. Strassfeld for proofreading and providing helpful suggestions in preparing the manuscript; Z. Li and Y.-K. Lin for proofreading supplementary information and repeating reactions; M. Gembicky and J. Bailey of the UCSD Crystallography Facility for X-ray crystallographic analysis; D.-H. Huang, L. Pasternack and G. Kroon of the Nuclear Magnetic Resonance Facility of the Scripps Researcher Services for their assistance with NMR analysis; and B. Webb and E. Billings of the Scripps Center for Metabolomics and Mass Spectrometry and Q. N. Wong of the Scripps Automated Synthesis Facility for assistance with mass spectrometry. This paper is dedicated to the memory of the late Dong-Hui Wang.
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J.-Q.Y. conceived the concept. S.Z. and Z.-J.Z. discovered and developed the dehydrogenation/lactonization reaction. S.Z. and Z.-J.Z. conducted the mechanistic studies. S.Z., Z.-J.Z. and J.-Q.Y. wrote the manuscript. J.-Q.Y. directed the project.
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J.-Q.Y., S.Z. and Z.-J.Z. are inventors on a patent application related to this work (US Patent application 63/605,065) filed by The Scripps Research Institute. The remaining authors declare no competing interests.
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Extended data figures and tables
Extended Data Fig. 1 Continued Substrate scope for the dehydrogenation reaction.
Reaction conditions: A (0.1 mmol), CuF2 (10 mol%), AcOH (8 eq.) or CSA (0.5 eq.), dioxane (0.50 mL), at 100-125 °C for 2-20 h (see the SI for details). Isolated yields are reported. aL (20 mol%) was added. bThe solvent is DCE. rr is the ratio of γ,δ-alkene/β,γ-alkene.
Extended Data Fig. 2 Continued substrate scope for the lactonization reaction.
Reaction conditions: A (0.1 mmol), CuF2 (10 mol%) or [(CH3CN)4Cu]BF4 (10 mol%), TFA (5 eq.), dioxane (0.50 mL), at 125 °C for 1-20 h (see the SI for details). Isolated yields are reported. aThe solvent is dioxane/MeNO2 (0.25 mL/0.25 mL). aThe acid is TsOH•H2O (1 eq.). b0.5 eq. CSA was used. c2.5 eq. TFA was used. d.r. = diastereomer ratio, see the SI for details.
Extended Data Fig. 3 Mechanistic studies.
(a) Investigation of Cu(I) generated in-situ. (b) Radical clock experiment. (c) Inverted regioselectivity of elimination from a cationic intermediate. See the SI for details.
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Supplementary Information
Supplementary Figs. 1–19, Tables 1–8 and references.
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Zhou, S., Zhang, ZJ. & Yu, JQ. Copper-catalysed dehydrogenation or lactonization of C(sp3)–H bonds. Nature 629, 363–369 (2024). https://doi.org/10.1038/s41586-024-07341-z
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DOI: https://doi.org/10.1038/s41586-024-07341-z
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