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  • Review Article
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Catalytic desymmetrization reactions to synthesize all-carbon quaternary stereocentres

Nature Synthesis volume 2, pages 1020–1036 (2023)Cite this article

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Abstract

The term all-carbon quaternary stereocentre refers to a chiral carbon atom featuring four different carbon substituents. Such structural motifs are prominent in natural products, drugs and bioactive compounds. Incorporating such conformationally constrained stereocentres into molecules allows the exploration of chemical spaces with enhanced potency, selectivity and other drug-related properties. Exploiting efficient catalytic enantioselective methods to construct all-carbon quaternary stereocentres is highly desirable for drug discovery, but constitutes a long-term challenge in organic synthesis. The desymmetrization strategy has been established as a powerful approach to this end and has found wide application in the total synthesis of natural products and bioactive compounds. The attractive features of this approach include its use of symmetric substrates that can be relatively easily prepared and that endow the products with a synthetic handle for further diversification, alleviating the steric repulsion that needs to be overcome to construct quaternary carbons, creating multiple stereocentres via one manipulation, and putting a wide range of catalytic reactions to use. This Review highlights the key advances in this area during the period 2016–2022, points out the challenges to be overcome, and outlines the synthetic opportunities still to be explored.

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Fig. 1: Towards all-carbon quaternary stereocentres.
Fig. 2: Various desymmetric reactions of 1,3-diketones.
Fig. 3: Desymmetric reactions of prochiral malonic acid and derivatives and malononitriles.
Fig. 4: Desymmetrization of cyclobutanones.
Fig. 5: Desymmetric transformations of small rings.
Fig. 6: Desymmetrization of prochiral enones.
Fig. 7: Desymmetric transformations of 4,4-disubstituted cyclopentene.
Fig. 8: Miscellaneous desymmetrization reactions.

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Acknowledgements

We are grateful for financial support from the NSFC (21971067, 22171090), the National Key Research and Development Program of China (2020YFA0710200), the Shanghai Science and Technology Innovation Action Plan (20JC1416900), the Innovation Program of Shanghai Municipal Education Commission (2023ZKZD37) and the Key Research and Development Program of Hubei Province (2022BAD083).

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Authors and Affiliations

  1. State Key Laboratory of Molecular & Process Engineering, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China

    Pengwei Xu, Feng Zhou & Jian Zhou

  2. School of Chemistry and Materials Science, Hubei Engineering University, Xiaogan, China

    Lei Zhu

  3. State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China

    Jian Zhou

  4. College of Chemistry and Molecular Sciences, Henan University, Kaifeng, China

    Jian Zhou

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  1. Pengwei Xu
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P.X., F.Z., L.Z and J.Z. contributed to the discussion and wrote the manuscript.

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Correspondence to Feng Zhou, Lei Zhu or Jian Zhou.

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Xu, P., Zhou, F., Zhu, L. et al. Catalytic desymmetrization reactions to synthesize all-carbon quaternary stereocentres. Nat. Synth 2, 1020–1036 (2023). https://doi.org/10.1038/s44160-023-00406-3

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