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  • Review Article
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Synthetic approaches to 1,4-dicarbonyl compounds

Nature Synthesis volume 1, pages 923–935 (2022)Cite this article

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Abstract

The synthesis of 1,4-dicarbonyls is a considerable challenge to organic chemists. While classical strategies to form 1,n-dioxygenated fragments, in which n is an odd number, are based on natural polarity, such that synthetic approaches are intuitive, the synthesis of 1,4-dicarbonyl moieties is more challenging and therefore less easily conceptualized. Owing to the intrinsic mismatch of the carbonyl polarity, 1,4-dicarbonyl compounds are a welcome retrosynthetic challenge to the creativity of synthetic chemists. Over the past decades, this problem has been addressed by multiple methods, which include organocatalytic Stetter reactions, oxidative enolate coupling and Claisen rearrangement–cleavage cascades, which all show remarkable levels of stereocontrol. Recent advances in forming 1,4-dicarbonyls largely focused on radical Stetter-type approaches or enolate umpolung reactions employing enolonium intermediates, as well as other methodologies that use non-carbonyl precursors. These routes give rise to the array of procedures presented in this Review. The Review also provides examples from natural product synthesis, which show that—despite the considerable advances in the field—there is still no singular, broadly applicable solution to the challenge of 1,4-dicarbonyl synthesis.

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Fig. 1: Examples of valuable 1,4-dicarbonyl compounds and the associated retrosynthetic challenges.
Fig. 2: Synthesis of 1,4-dicarbonyls using two-electron processes via the C1,C2 disconnection (0 + 2 electron coupling).
Fig. 3: Different approaches to 1,4-dicarbonyl synthesis using a radical 1,2-retrosynthetic disconnection (1 + 1 electron coupling).
Fig. 4: Different approaches to 1,4-dicarbonyl synthesis through σ-bond formation between carbon atoms 2 and 3.
Fig. 5: Different approaches to 1,4-dicarbonyl synthesis through two-electron coupling between carbon atoms 2 and 3 (2 + 2 electron coupling).
Fig. 6: Different approaches to 1,4-dicarbonyls from non-carbonyl precursors through sigmatropic rearrangements and enyne hydration as well as a photoredox-catalysed approach.
Fig. 7: Application of 1,4-dicarbonyl syntheses in the context of total synthesis (I).
Fig. 8: Application of 1,4-dicarbonyl syntheses in the context of total synthesis (II).

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Acknowledgements

Generous support by the ERC (CoG VINCAT 682002 to N.M.) is acknowledged. We are also grateful to the University of Vienna and the Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences for continued support of our research programmes.

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  1. These authors contributed equally: Miran Lemmerer, Manuel Schupp.

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  1. Institute of Organic Chemistry, University of Vienna, Vienna, Austria

    Miran Lemmerer, Manuel Schupp, Daniel Kaiser & Nuno Maulide

  2. CeMM—Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria

    Manuel Schupp & Nuno Maulide

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M.L., M.S., D.K. and N.M. contributed to the discussions and wrote the manuscript.

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Lemmerer, M., Schupp, M., Kaiser, D. et al. Synthetic approaches to 1,4-dicarbonyl compounds. Nat. Synth 1, 923–935 (2022). https://doi.org/10.1038/s44160-022-00179-1

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