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  • Review Article
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Chiral medium-sized rings beyond central chirality

Nature Reviews Chemistry volume 9, pages 617–633 (2025)Cite this article

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Abstract

Chiral medium-sized rings (MSRs), cyclic molecular structures comprising 7–11-membered rings, are prevalent in bioactive molecules owing to their unique three-dimensional structures and pharmacological properties. Compared with the extensively studied central chirality, MSRs with unconventional chirality — that is, axial chirality, inherent chirality and planar chirality — remain underexplored. The past decade has witnessed rapid advances in this field, with breakthroughs in their synthesis and applications. This Review is structured around the three underexplored types of chirality exhibited in MSRs detailing their key synthetic strategies, with a critical evaluation of their advantages and limitations. Additionally, the factors that influence the conformational stability of chiral MSRs are discussed using structure and energy analysis.

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Fig. 1: General strategies in the synthesis of chiral MSRs and their importance.
Fig. 2: Construction of axially chiral medium-sized rings (MSRs) derived from cyclic substrates.
Fig. 3: Construction of axially chiral medium-sized rings (MSRs) via cyclization strategy.
Fig. 4: Construction of allene-type axially chiral medium-sized rings (MSRs).
Fig. 5: Construction of inherently chiral medium-sized rings (MSRs) via a de novo cyclization strategy.
Fig. 6: Asymmetric synthesis of inherently chiral medium-sized rings (MSRs) through cyclic substrate transformation.
Fig. 7: Asymmetric synthesis of planar chiral medium-sized rings (MSRs).

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Acknowledgements

We acknowledge the China Postdoctoral Science Foundation (grant number 2023M733212), Henan Provincial Science and Technology Research and Development Program Joint Fund (Advantageous Discipline Cultivation Category) Project (242301420049), the Ministry of Science and Technology of the People’s Republic of China, and the Open Research Fund of State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University. We deeply appreciate the invaluable guidance and support provided by G. Yin from Wuhan University during the preparation of this manuscript.

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  1. Department of Chemistry, Zhengzhou University, Zhengzhou, China

    Shiqi Jia  (贾师琦), Yudong Hao  (郝育栋), Yuedi Li  (李月迪) & Yu Lan  (蓝宇)

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S.J., Y.H. and Y. Li contributed to the literature search and the preparation of figures. S.J. conceived and wrote the project under the guidance of Y. Lan. All authors contributed to editing the manuscript before submission.

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Correspondence to Shiqi Jia  (贾师琦) or Yu Lan  (蓝宇).

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Jia, S., Hao, Y., Li, Y. et al. Chiral medium-sized rings beyond central chirality. Nat Rev Chem 9, 617–633 (2025). https://doi.org/10.1038/s41570-025-00735-1

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