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Palladium-catalysed branch- and enantioselective allylic C–H alkylation of α-alkenes

Nature Synthesis volume 1, pages 487–496 (2022)Cite this article

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Abstract

Enantioselective functionalization of alkenes is an attractive and straightforward method to assemble molecular complexity from readily available chemical feedstocks. Although regio- and enantioselective transformations of the C=C bond of alkenes have been extensively studied, those of the allylic C–H bonds of unactivated alkenes are yet to be explored. Here we report a palladium-catalysed branch- and enantioselective allylic C–H alkylation that is capable of accommodating diverse types of α-alkenes, ranging from feedstocks annually manufactured on a million-tonne scale to olefins tethering a wide scope of appended functionalities, providing unconventional access to chiral γ,δ-unsaturated amides. Notably, mechanistic studies reveal that regioselectivity is not only governed by the coordination pattern of nucleophiles but also regulated by the ligational behaviours of ligands, highlighting the importance of the monoligation of chiral phosphoramidite ligands in provoking high levels of stereo- and branch-selectivity via a nucleophile coordination-enabled inner-sphere allylation pathway.

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Fig. 1: Asymmetric allylic C–H functionalization of α-alkenes.
Fig. 2: Asymmetric allylic C−H alkylation catalysed by palladium-phosphoramidite complex.
Fig. 3: Synthetic applications of chiral α-alkylated products.
Fig. 4: Mechanistic investigation.
Fig. 5: DFT-computed relative energy profiles of plausible inner-sphere pathways.

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Data availability

All data generated or analysed during this study are included in this published article and its Supplementary Information. Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition no. CCDC 2142298 (16). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

We gratefully acknowledge the financial support from the NSFC (grant nos. 22188101), Youth Innovation Promotion Association CAS and Anhui Provincial Natural Science Foundation (grant no. 2108085MB58).

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  1. These authors contributed equally: Zhong-Sheng Nong, Ling Zhu.

Authors and Affiliations

  1. Department of Chemistry, University of Science and Technology of China, Hefei, China

    Zhong-Sheng Nong, Ling Zhu, Tian-Ci Wang, Lian-Feng Fan, Pu-Sheng Wang & Liu-Zhu Gong

  2. Center for Excellence in Molecular Synthesis of Chinese Academy of Sciences, Hefei, China

    Liu-Zhu Gong

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Contributions

Z.-S.N., P.-S.W. and L.-Z.G. conceived the project. Z.-S.N., T.-C.W. and L.-F.F. performed the experiments and analysed the data. L.Z. and P.-S.W. designed and performed the DFT calculations. P.-S.W. and L.-Z.G. supervised the research and co-wrote the manuscript.

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Correspondence to Pu-Sheng Wang or Liu-Zhu Gong.

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Nature Synthesis thanks Per-Ola Norrby and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling editor: Thomas West, in collaboration with the Nature Synthesis team.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–20, Discussion, NMR spectra, HPLC data, references and Tables 1–12.

Supplementary Data 1

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Supplementary Data 2

Crystallographic data for compound 16 CCDC 2142298

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Nong, ZS., Zhu, L., Wang, TC. et al. Palladium-catalysed branch- and enantioselective allylic C–H alkylation of α-alkenes. Nat. Synth 1, 487–496 (2022). https://doi.org/10.1038/s44160-022-00084-7

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