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Stereoselective conjugate cyanation of enals by combining photoredox and organocatalysis

Nature Catalysis volume 6, pages 332–338 (2023)Cite this article

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Abstract

Precise control over the selectivity of a reaction is a fundamental target. While great advances have been obtained in achieving stereocontrol, the selective manipulation of functional groups within a substrate (chemoselectivity) is still a challenge. The cyanation of aldehydes offers an illustrative example: the 1,2-addition of nucleophilic cyanide to the aldehydic group was one of the first examples of a stereoselective catalytic process. By contrast, the conjugate cyanation of linear α,β-unsaturated aldehydes has remained elusive, even in a racemic variant. The main difficulty lies in achieving 1,4-chemoselectivity over the preferred cyanide 1,2-addition. Here, we report an asymmetric catalytic method to achieve the exclusive conjugate cyanation of enals. The synergistic action of a chiral organocatalyst with a visible-light-activated photoredox catalyst promotes the single-electron reduction of enals, inducing a formal inversion of polarity. The resulting chiral radical, being nucleophilic in character, is then intercepted by an electrophilic cyanide source with perfect 1,4-chemoselectivity and good stereocontrol.

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Fig. 1: Asymmetric catalytic cyanation of aldehydes and their unsaturated counterparts.
Fig. 2: Initial explorations and mechanistic proposal.
Fig. 3: Organocatalytic asymmetric conjugate cyanation of enals.
Fig. 4: Generality of the umpolung strategy of enals and mechanistic considerations.

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Data availability

Materials and methods, experimental procedures, useful information, mechanistic studies, 1H NMR spectra, 13C NMR spectra and mass spectrometry data are available in Supplementary Information. Raw data are available from the corresponding author on reasonable request. Crystallographic data for the acylated derivatives of compounds 3d and 7e have been deposited with the Cambridge Crystallographic Data Centre, accession numbers CCDC 2197381 and 2197380, respectively.

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Acknowledgements

Financial support was provided by the Ministry for Science and Innovation AEI/10.13039/501100011033 (CEX2019-000925-S) and Agencia Estatal de Investigación (PID2019-106278GB-I00). M.B. thanks the Austrian Science Foundation (FWF, J4603-N) for an Erwin-Schrödinger postdoctoral fellowship. Y.B. thanks the Swiss National Science Foundation (P2BSP2_200098) for a postdoctoral fellowship. D.M. thanks the European Union for a Horizon 2020 Marie Skłodowska-Curie Fellowship (H2020-MSCA-IF-2019 894795). T.H.-F.W. thanks the Government of Catalonia for an FI Fellowship (2021FI−B00304). We thank P. Capurro for preliminary investigations, M. Martinez and J. Benet for X-ray crystallographic analysis and M. Giménez and C. Rivero for assistance with ozonolysis and hydrogenation experiments.

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Author notes

  1. These authors contributed equally: Martin Berger, Dengke Ma, Yann Baumgartner.

Authors and Affiliations

  1. ICIQ, Institute of Chemical Research of Catalonia, Barcelona Institute of Science and Technology, Tarragona, Spain

    Martin Berger, Dengke Ma, Yann Baumgartner & Thomas Hin-Fung Wong

  2. Department of Industrial Chemistry ‘Toso Montanari’, University of Bologna, Bologna, Italy

    Paolo Melchiorre

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Contributions

M.B., Y.B. and T.H.-F.W. developed the reaction, investigated the substrate scope and studied the reaction mechanism. D.M. first observed the reactivity and performed the initial screening. All authors contributed to the experimental design and the interpretation of data. P.M. conceived and supervised the project. M.B., Y.B. and P.M. directed the project. M.B. and P.M. wrote the paper with input from all authors.

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Correspondence to Paolo Melchiorre.

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Supplementary information

Supplementary Information

Supplementary Table 1, Methods and References.

Supplementary Data 1

Crystallographic data of acylated derivative of compound 3d.

Supplementary Data 2

Crystallographic data of acylated derivative of compound 7e.

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Berger, M., Ma, D., Baumgartner, Y. et al. Stereoselective conjugate cyanation of enals by combining photoredox and organocatalysis. Nat Catal 6, 332–338 (2023). https://doi.org/10.1038/s41929-023-00939-y

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