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Switchable regioselectivity in amine-catalysed asymmetric cycloadditions

Nature Chemistry volume 9, pages 590–594 (2017)Cite this article

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Abstract

Building small-molecule libraries with structural and stereogenic diversity plays an important role in drug discovery. The development of switchable intermolecular cycloaddition reactions from identical substrates in different regioselective fashions would provide an attractive protocol. However, this also represents a challenge in organic chemistry, because it is difficult to control regioselectivity to afford the products exclusively and at the same time achieve high levels of stereoselectivity. Here, we report the diversified cycloadditions of α′-alkylidene-2-cyclopentenones catalysed by cinchona-derived primary amines. An asymmetric γ,β′-regioselective intermolecular [6+2] cycloaddition reaction with 3-olefinic (7-aza)oxindoles is realized through the in situ generation of formal 4-aminofulvenes, while a different β,γ-regioselective [2+2] cycloaddition reaction with maleimides to access fused cyclobutanes is disclosed. In contrast, an intriguing α,γ-regioselective [4+2] cycloaddition reaction is uncovered with the same set of substrates, by employing an unprecedented dual small-molecule catalysis of amines and thiols. All of the cycloaddition reactions exhibit excellent regio- and stereoselectivity, producing a broad spectrum of chiral architectures with high structural diversity and molecular complexity.

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Figure 1: Overview of [6+2] cycloadditions with fulvenes and outlines of distinct regioselective cycloaddition patterns of α′-alkylidene-2-cyclopentenones via aminocatalysis.
Figure 2: Discovery of switchable [4+2] cycloadditions via amine and thiol dual catalysis.

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Acknowledgements

The authors acknowledge financial support from the Natural Science Foundation of China (grant numbers 21125206, 21372160 and 21321061).

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Authors and Affiliations

  1. Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China

    Zhi Zhou, Zhou-Xiang Wang, Yuan-Chun Zhou, Wei Xiao, Wei Du & Ying-Chun Chen

  2. College of Pharmacy, Third Military Medical University, Chongqing, 400038, China

    Qin Ouyang & Ying-Chun Chen

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  1. Zhi Zhou
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Contributions

Z.Z. and Y.C.C conceived and designed the research. Z.Z., Z.X.W., Y.C.Z. and W.X. performed the research. Q.O. performed the DFT computational calculation study. Y.C.C., Q.O., W.D. and Z.Z. co-wrote the paper.

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Correspondence to Qin Ouyang or Ying-Chun Chen.

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Supplementary information

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Supplementary information (PDF 14020 kb)

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Crystallographic data for compound 3b. (CIF 326 kb)

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Crystallographic data for compound 4b. (CIF 643 kb)

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Crystallographic data for compound 9b. (CIF 379 kb)

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Zhou, Z., Wang, ZX., Zhou, YC. et al. Switchable regioselectivity in amine-catalysed asymmetric cycloadditions. Nature Chem 9, 590–594 (2017). https://doi.org/10.1038/nchem.2698

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