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Copper-catalysed convergent regio- and enantioselective alkynylallylic substitution

Nature Synthesis volume 2, pages 37–48 (2023)Cite this article

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Abstract

Asymmetric allylic and propargylic substitutions have seen numerous applications in synthetic chemistry, constructing stereogenic centres vicinal to unsaturated C–C bonds. However, the merger of these two substitution processes into alkynylallylic substitution is relatively underdeveloped, probably owing to the challenge of controlling regio- and stereoselectivity. Here we report the development of enantioselective intermolecular and decarboxylative alkynylallylic aminations, alkoxylation and alkylation for the synthesis of a range of enantioenriched 1,4-enynes. Cu(I) and Cu(II) salts are both effective precatalysts for the process, which can also be readily performed on a gram scale in the presence of air and moisture with no erosion in yield or selectivity. The convergent nature of the process was shown through the synthesis of a single product from a mixture of eight regio- and enantiomeric alkynylallylic carbamates and carbonate substrates, in excellent yield and selectivity. X-ray crystallographic and mechanistic analysis reveal that the Cu(I) and Cu(II) processes probably proceed through distinct enantio-determining transition state models, involving multiple ligands.

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Fig. 1: Background and our concept.
Fig. 2: Established reaction conditions and preliminary mechanistic studies of different copper catalysts.
Fig. 3: Additional mechanistic experiments with the Cu(I) system and the proposed mechanism.
Fig. 4: Robustness tests and synthetic applications.
Fig. 5: Convergent synthesis and alkynylallylic alkoxylation and alkylation.

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Data availability

All relevant data are available within the Article or in the Supplementary Information files. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition number CCDC 2100528 (rac-3a), 2155927 (C-1), 2143688 (C-2) and 2155930 (C-3).

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Acknowledgements

We acknowledge the National Natural Science Foundation of China (grant nos. NSFC 22071262 to Z.-T.H., and 22101296, 21871284 and 91956113 to G.-Q.L.), the Shanghai Rising-Star programme (grant no. 20QA1411300 to Z.-T.H.), the Shanghai Municipal Committee of Science and Technology (grant no. 22ZR1475200 to Z.-T.H.), the CAS Key Laboratory of Synthetic Chemistry of Natural Substances and the Shanghai Institute of Organic Chemistry for financial support. H. Luo and X.-S. Xue are thanked for help with preliminary trials and discussions on Density Functional Theory calculations.

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  1. These authors contributed equally: Jiang-Shan Ma, Han-Yu Lu.

Authors and Affiliations

  1. CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Shanghai, China

    Jiang-Shan Ma, Han-Yu Lu, Ye-Wei Chen, Wei-Cheng Zhao, Yu-Ze Sun, Rui-Peng Li, Hu-Xiao Wang, Guo-Qiang Lin & Zhi-Tao He

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

    Han-Yu Lu, Ye-Wei Chen & Guo-Qiang Lin

  3. School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China

    Zhi-Tao He

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Contributions

Z.-T.H. conceived the project. J.-S.M., H.-Y.L., Y.-W.C., Y.-Z.S., W.-C.Z., R.-P.L. and H.-X.W. performed the experiments. G.-Q.L. and Z.-T.H. supervised the project. Z.-T.H. wrote the manuscript with feedback from all authors.

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Correspondence to Guo-Qiang Lin or Zhi-Tao He.

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Nature Synthesis thanks Jan van Maarseveen 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. 1–176 and Tables 1–14.

Supplementary Data 1

X-ray crystallographic data for C-1, CCDC 2155927.

Supplementary Data 2

X-ray crystallographic data for C-2, CCDC 2143688.

Supplementary Data 3

X-ray crystallographic data for C-3, CCDC 2155930.

Supplementary Data 4

X-ray crystallographic data for rac-3a, CCDC 2100528.

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Ma, JS., Lu, HY., Chen, YW. et al. Copper-catalysed convergent regio- and enantioselective alkynylallylic substitution. Nat. Synth 2, 37–48 (2023). https://doi.org/10.1038/s44160-022-00176-4

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