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Synthetic techniques for thermodynamically disfavoured substituted six-membered rings

Nature Reviews Chemistry volume 8, pages 535–550 (2024)Cite this article

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Abstract

Six-membered rings are ubiquitous structural motifs in bioactive compounds and multifunctional materials. Notably, their thermodynamically disfavoured isomers, like disubstituted cyclohexanes featuring one substituent in an equatorial position and the other in an axial position, often exhibit enhanced physical and biological activities in comparison with their opposite isomers. However, the synthesis of thermodynamically disfavoured isomers is, by its nature, challenging, with only a limited number of possible approaches. In this Review, we summarize and compare synthetic methodologies that produce substituted six-membered rings with thermodynamically disfavoured substitution patterns. We place particular emphasis on elucidating the crucial stereoinduction factors within each transformation. Our aim is to stimulate interest in the synthesis of these unique structures, while simultaneously providing synthetic chemists with a guide to approaching this synthetic challenge.

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Fig. 1: Comparison between thermodynamically favoured and disfavoured disubstituted cyclohexanes.
Fig. 2: Hydrogenation reactions for the synthesis of thermodynamically disfavoured cyclohexanes.
Fig. 3: Metal-catalysed hydrogenation of substituted arenes.
Fig. 4: Transition metal-catalysed functionalization of alkenes.
Fig. 5: Diels–Alder cyclization reactions, and metal-catalysed and photo-promoted cyclization reactions.
Fig. 6: C–H functionalizations of substituted cyclohexanes.
Fig. 7: Synthesis of thermodynamically disfavoured substituted piperidines.

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Acknowledgements

We acknowledge the National Natural Science Foundation of China (22122107), the Fundamental Research Funds for Central Universities (2042022kf1023) and Wuhan University for financial support.

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  1. These authors contributed equally: Yangyang Li, Hongjin Shi.

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  1. The Institute for Advanced Studies, Wuhan University, Wuhan, Hubei Province, China

    Yangyang Li, Hongjin Shi & Guoyin Yin

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Y.L. and H.S. contributed to the literature search and the preparation of figures. Y.L. and G.Y. wrote the article. All authors contributed to editing the manuscript prior to submission. G.Y. conceived and directed the project.

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Correspondence to Guoyin Yin.

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Li, Y., Shi, H. & Yin, G. Synthetic techniques for thermodynamically disfavoured substituted six-membered rings. Nat Rev Chem 8, 535–550 (2024). https://doi.org/10.1038/s41570-024-00612-3

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