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Gold-catalysed asymmetric net addition of unactivated propargylic C–H bonds to tethered aldehydes

Nature Catalysis volume 4, pages 164–171 (2021)Cite this article

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Abstract

The asymmetric one-step net addition of unactivated propargylic C–H bonds to aldehydes leads to an atom-economic construction of versatile chiral homopropargylic alcohols, but has not yet been realized. Here we show its implementation in an intramolecular manner under mild reaction conditions. This chemistry—via cooperative gold catalysis enabled by a chiral bifunctional phosphine ligand—achieves asymmetric catalytic deprotonation of propargylic C–H (pKa > 30) by a tertiary amine group (pKa ≈ 10) of the ligand in the presence of much more acidic aldehydic α-hydrogens (pKa ≈ 17). The reaction exhibits a broad scope and readily accommodates various functional groups. The cyclopentane/cyclohexane-fused homopropargylic alcohol products are formed with excellent enantiomeric excesses and high trans-selectivities with or without a preexisting substrate chiral centre. Density functional theory studies of the reaction support the conceived reaction mechanism and the calculated energetics corroborate the observed stereoselectivity and confirm additional metal–ligand cooperation.

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Fig. 1: Asymmetric propargylation of aldehydes.
Fig. 2: Oak Ridge thermal ellipsoid plots of crystal structures.
Fig. 3: DFT-calculated energetics of the reaction of 3a in DCE.
Fig. 4: Further transformations of the products.

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Data availability

Experimental procedures, characterization of compounds and DFT calculations are available in the Supplementary Information. The X-ray diffraction data for 11, 6p and (S)-L3AuCl are deposited to the Cambridge Crystallographic Data Centre (CCDC) with the reference numbers 1988012, 1988013 and 1988482, respectively. All data are available from the authors on reasonable request.

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Acknowledgements

L.Z. thanks NIH (grant no. R01GM123342) and NSF CHE (grant no. 1800525) for financial support, and NSF (grant no. MRI-1920299) for the acquisition of Bruker 500 MHz and 400 MHz NMR instruments. The DFT studies were performed using the computational facilities purchased with funds from the National Science Foundation (grant no. CNS-1725797) and administered by the Center for Scientific Computing (CSC). The CSC is supported by the California NanoSystems Institute and the Materials Research Science and Engineering Center (MRSEC; NSF grant no. DMR 1720256) at UC Santa Barbara.

Author information

Author notes

  1. Ting Li

    Present address: College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang, Henan, P. R. China

  2. These authors contributed equally: Ting Li, Xinpeng Cheng.

Authors and Affiliations

  1. Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, USA

    Ting Li, Xinpeng Cheng & Liming Zhang

  2. Key Laboratory of Environmental Functional Materials Technology and Application of Wenzhou City, College of Chemistry & Materials Engineering, Institute of New Materials & Industry Technology, Wenzhou University, Wenzhou, China

    Ting Li & Pengcheng Qian

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  1. Ting Li
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  2. Xinpeng Cheng
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  4. Liming Zhang
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Contributions

T.L. conducted the experiments and prepared a draft of the manuscript. X.C. synthesized the ligands and their gold catalysts and helped with the manuscript. P.Q. secured a postdoctoral fellowship from Wenzhou University for T.L. and participated in the chemistry design. L.Z. designed the chemistry and supervised its implementation and finalized the manuscript.

Corresponding authors

Correspondence to Pengcheng Qian or Liming Zhang.

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The authors declare no competing interests.

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Peer review information Nature Catalysis thanks Ryan Vander Linden and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Experimental procedures, DFT-optimized structure coordinates, X-ray diffraction data, chiral HPLC chromatographs and NMR spectra.

Supplementary Data 1

X-ray crystal data of compound 11.

Supplementary Data 2

X-ray crystal data of compound 6p.

Supplementary Data 3

X-ray crystal data of compound (S)-L3AuCl.

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Li, T., Cheng, X., Qian, P. et al. Gold-catalysed asymmetric net addition of unactivated propargylic C–H bonds to tethered aldehydes. Nat Catal 4, 164–171 (2021). https://doi.org/10.1038/s41929-020-00569-8

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