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Catalytic multicomponent reaction involving a ketyl-type radical

Nature Synthesis volume 1, pages 464–474 (2022)Cite this article

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Abstract

The development of new strategies and concepts towards the synthetic utilization of carbonyl compounds is of pivotal relevance. Nevertheless, the generation of ketyl radicals requires relatively harsh conditions and a large excess of reductants, which represents a long-standing, unsolved problem that hampers the broad application of ketyl coupling processes. Several catalytic approaches have been developed to generate ketyl radicals and successfully applied in reductive cyclizations and two-component cross-coupling reactions. However, catalytic multicomponent reactions that involve a ketyl radical remain rare, but are in high demand owing to their ability to rapidly generate complexity in molecules. Here we report a multicomponent, redox-neutral photocatalytic manifold that combines readily available aldehydes, feedstock 1,3-butadiene and various nucleophiles to build architecturally complex and functionally diverse homoallylic alcohols in one pot. This operationally straightforward method exhibits a wide functional group tolerance, enables the synthesis of drug-like architectures that are not readily accessible by other methods and is applied towards key intermediates of several natural products, which makes the strategy of broad interest in areas such as synthetic and medicinal chemistry.

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Fig. 1: Development of a strategy for a catalytic MCR that involves ketyl radicals.
Fig. 2: Optimization of a MCR that involves ketyl-type radicals.
Fig. 3: Mechanistic studies.
Fig. 4: Computational calculations.
Fig. 5: Synthetic application of the methodology towards total synthesis and the generation of complex heterocyclic motifs.

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Data availability

Materials and methods, detailed optimization studies, experimental procedures, mechanistic studies, DFT calculation details and NMR spectra are available in the Supplementary Information and from the corresponding authors upon reasonable request. NMR spectroscopy data in JCAMP-DX format, Cartesian coordinates of the DFT-optimized structures, step-by-step set-up pictures and ultraviolet–visible and fluorescence spectroscopy data are available at Zenodo under the Creative Commons Attribution 4.0 International license: https://doi.org/10.5281/zenodo.6425457.

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Acknowledgements

We thank the Alexander von Humboldt Foundation and the start-up funding from ShanghaiTech University (H.-M.H.), the Deutsche Forschungsgemeinschaft (Leibniz Award, F.G.; SBF 858, P.B.) and the Institute for Basic Science (IBS-R010-D1, S.K.) of the Republic of Korea for generous financial support. We thank Prof. S. Chang (KAIST) for the kind support of this work, and M.J. Milner, J. E. Erchinger and S. Heuvel (WWU Münster) are acknowledged for experimental assistance.

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  1. These authors contributed equally: Huan-Ming Huang, Peter Bellotti.

Authors and Affiliations

  1. Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Münster, Germany

    Huan-Ming Huang, Peter Bellotti, Xiaolong Zhang & Frank Glorius

  2. School of Physical Science and Technology, ShanghaiTech University, Shanghai, China

    Huan-Ming Huang

  3. Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea

    Suhyeon Kim

  4. Center for Catalytic Hydrocarbon Functionalization, Institute for Basic Science (IBS), Daejeon, Korea

    Suhyeon Kim

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Contributions

H.-M.H. and F.G. conceived the project and supervised the research. H.-M.H. and P.B. performed all of the experiments and analysed all of the data. X.Z. performed the cyclic voltammetry data acquisition and analysis. S.K. performed the DFT calculations. H.-M.H., P.B., S.K. and F.G. co-wrote the manuscript.

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Correspondence to Huan-Ming Huang or Frank Glorius.

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Supplementary Sections 1–14, experimental details, Figs. 1–30, Tables 1–11 and NMR spectra.

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Huang, HM., Bellotti, P., Kim, S. et al. Catalytic multicomponent reaction involving a ketyl-type radical. Nat. Synth 1, 464–474 (2022). https://doi.org/10.1038/s44160-022-00085-6

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