Abstract
Modern retrosynthetic analysis in organic chemistry is based on the principle of polar relationships between functional groups to guide the design of synthetic routes1. This method, termed polar retrosynthetic analysis, assigns partial positive (electrophilic) or negative (nucleophilic) charges to constituent functional groups in complex molecules followed by disconnecting bonds between opposing charges2,3,4. Although this approach forms the basis of undergraduate curriculum in organic chemistry5 and strategic applications of most synthetic methods6, the implementation often requires a long list of ancillary considerations to mitigate chemoselectivity and oxidation state issues involving protecting groups and precise reaction choreography3,4,7. Here we report a radical-based Ni/Ag-electrocatalytic cross-coupling of substituted carboxylic acids, thereby enabling an intuitive and modular approach to accessing complex molecular architectures. This new method relies on a key silver additive that forms an active Ag nanoparticle-coated electrode surface8,9 in situ along with carefully chosen ligands that modulate the reactivity of Ni. Through judicious choice of conditions and ligands, the cross-couplings can be rendered highly diastereoselective. To demonstrate the simplifying power of these reactions, concise syntheses of 14 natural products and two medicinally relevant molecules were completed.
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The data that support the findings in this work are available within the paper and in the Supplementary Information.
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Acknowledgements
We are grateful to D.-H. Huang and L. Pasternack (Scripps Research) for nuclear magnetic resonance spectroscopic assistance and J. Chen and Q. Nguyen Wong (Scripps Automated Synthesis Facility) for assistance with high-resolution mass spectrometry. Financial support for this work was provided by the National Science Foundation Center for Synthetic Organic Electrochemistry (grant CHE-2002158 for optimization of reactivity and initial scope) and the National Institutes of Health (grant GM-118176 for the application of the method to natural product synthesis). We also thank the George E. Hewitt Foundation (to G.L.) for support.
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B.Z., Y.K. and P.S.B. conceptualized the study. B.Z., J.H., Y.G., L.L., M.S.O., M.D.P., C.B. and Y.K. performed the experimental investigation. B.Z., J.H., Y.G., L.L., M.S.O., M.D.P., T.G.M.D., M.D.M., M.R.C., D.C.S., P.N.B., T.C., S.C., N.N.P., G.L., Y.K. and P.S.B. performed data analysis. B.Z., J.H., Y.K. and P.S.B. wrote the manuscript. Y.K. and P.S.B. acquired funding. Y.K. and P.S.B. performed project administration.
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Zhang, B., He, J., Gao, Y. et al. Complex molecule synthesis by electrocatalytic decarboxylative cross-coupling. Nature 623, 745–751 (2023). https://doi.org/10.1038/s41586-023-06677-2
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DOI: https://doi.org/10.1038/s41586-023-06677-2
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