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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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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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.
The authors declare no competing interests.
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Supplementary Figs. 1–176 and Tables 1–14.
X-ray crystallographic data for C-1, CCDC 2155927.
X-ray crystallographic data for C-2, CCDC 2143688.
X-ray crystallographic data for C-3, CCDC 2155930.
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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