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Kinetically controlled Z-alkene synthesis using iron-catalysed allene dialkylation

Nature Synthesis (2024)Cite this article

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Abstract

Stereodefined trisubstituted alkenes are key constituents of biologically active molecules and also serve as indispensable substrates for a wide range of stereospecific reactions affording sp3-hybridized skeletons. However, there is a persisting lack of methods that generate the thermodynamically less stable Z-isomers. Here we report an iron-catalysed multicomponent strategy that merges allenes, dialkylzinc compounds and haloalkanes to construct trisubstituted alkenes with excellent control of regioselectivity and Z-selectivity. Selective installation of diverse C(sp3) groups enables access to a broad library of functionalized unsaturated products. The synthetic utility of the method is highlighted through the synthesis of a glucosylceramide synthase inhibitor. Contrary to conventional mechanisms for metal-catalysed allene functionalization, our studies suggest a kinetically controlled pathway involving sequential radical-mediated alkylferration of the less hindered C=C bond and inner-sphere alkylation via reductive elimination. Mechanistic and computational investigations reveal the origins of the stereochemical outcome.

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Fig. 1: Challenges and strategies for the synthesis of trisubstituted Z-alkenes.
Fig. 2: The scope of allenes in iron-catalysed 1,2-dialkylation.
Fig. 3: The scope of electrophiles and nucleophiles in iron-catalysed 1,2-dialkylation and its synthetic utility.
Fig. 4: Mechanistic and computational studies.

Data availability

All data supporting the findings of this study are available within the article and its Supplementary Information. The DFT-optimized structures are available via Zenodo at https://doi.org/10.5281/zenodo.11363682 (ref. 42).

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Acknowledgements

This research was supported by the Ministry of Education of Singapore Academic Research Fund Tier 2 (A-8000034-00-00, M.J.K.) and the Foundation of Wenzhou Science & Technology Bureau (ZY2020027, T.-D.T. and P.-C.Q.).

Author information

Author notes

  1. These authors contributed equally: Tong-De Tan, Kai Ze Tee.

  2. These authors jointly supervised this work: Xinglong Zhang, Ming Joo Koh.

Authors and Affiliations

  1. College of Chemistry & Materials Engineering, Wenzhou University, Wenzhou, China

    Tong-De Tan & Peng-Cheng Qian

  2. Department of Chemistry, National University of Singapore, Singapore, Republic of Singapore

    Tong-De Tan, Kai Ze Tee, Xiaohua Luo & Ming Joo Koh

  3. Department of Chemistry, The Chinese University of Hong Kong, Hong Kong, China

    Xinglong Zhang

  4. Institute of High-Performance Computing, Agency for Science, Technology and Research (A∗STAR), Singapore, Republic of Singapore

    Xinglong Zhang

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Contributions

M.J.K. and T.-D.T. conceived the project. T.-D.T., K.Z.T., X.L. and P.-C.Q. developed the catalytic method. X.Z. designed and performed the DFT studies. M.J.K. wrote the paper with revisions provided by the other authors.

Corresponding authors

Correspondence to Xinglong Zhang or Ming Joo Koh.

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Nature Synthesis thanks the anonymous reviewers for their contribution to the peer review of this work. Primary Handling Editor: Thomas West, in collaboration with the Nature Synthesis team.

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Supplementary information

Supplementary Information

Supplementary Tables 1–3, Figs. 1–10, experimental data, synthesis and characterization data, DFT calculation data, NMR spectra, and references.

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Tan, TD., Tee, K.Z., Luo, X. et al. Kinetically controlled Z-alkene synthesis using iron-catalysed allene dialkylation. Nat. Synth (2024). https://doi.org/10.1038/s44160-024-00658-7

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