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Enantioselectivity prediction of pallada-electrocatalysed C–H activation using transition state knowledge in machine learning

Nature Synthesis volume 2, pages 321–330 (2023)Cite this article

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Abstract

Enantioselectivity prediction in asymmetric catalysis has been a long-standing challenge in synthetic chemistry because of the high-dimensional nature of the structure–enantioselectivity relationship. A lack of understanding of the synthetic space results in laborious and time-consuming efforts in the discovery of asymmetric reactions, even if the same transformation has already been optimized on model substrates. Here we present a data-driven workflow to achieve a holistic enantioselectivity prediction of asymmetric pallada-electrocatalysed C–H activation by implementing transition state knowledge in machine learning. The vectorization of transition state knowledge allowed for an excellent description and extrapolation of the machine learning model, and enabled the quantitative evaluation of 846,720 possibilities. Model interpretation revealed the non-intuitive olefin effect on the enantioselectivity determination. Subsequent density functional theory calculations unravelled mechanistic knowledge that the rate-determining step depends on the olefin reactivity in the insertion step. Therefore, the olefin insertion step can be involved in the overall enantioselectivity determination. These results highlight the complementary features of knowledge-based machine learning with an interpretation-driven mechanistic study, which provides the opportunity to harness widely existing catalysis screening data and transition state models in molecular synthesis.

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Fig. 1: Prediction strategies for asymmetric catalysis.
Fig. 2: Workflow design for synthetic space prediction.
Fig. 3: Dataset of the pallada-electrocatalysed C–H olefination and design of TS model-based encoding.
Fig. 4: Regression performance of the designed ML model.
Fig. 5: Model interpretation and mechanistic study of the olefin effect.
Fig. 6: Synthetic space prediction and experimental verifications.

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Data availability

Data related to ML details, experimental procedures, HPLC spectra and NMR spectra are available in the Supplementary Information. Source data are provided with this paper.

Code availability

Codes for target transformation, descriptor generation, model training, feature selection, feature ranking and synthetic space exploration are freely available at https://github.com/licheng-xu-echo/SyntheticSpacePrediction.

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Acknowledgements

Generous support by the National Natural Science Foundation of China (21873081 and 22122109, X. Hong; 22103070, S.-Q.Z.), the Starry Night Science Fund of Zhejiang University Shanghai Institute for Advanced Study (SN-ZJU-SIAS-006, X. Hong), Beijing National Laboratory for Molecular Sciences (BNLMS202102, X. Hong), CAS Youth Interdisciplinary Team (JCTD-2021-11, X. Hong), Fundamental Research Funds for the Central Universities (226-2022-00140 and 226-2022-00224, X. Hong), the Center of Chemistry for Frontier Technologies and Key Laboratory of Precise Synthesis of Functional Molecules of Zhejiang Province (PSFM 2021-01, X. Hong), the State Key Laboratory of Clean Energy Utilization (ZJUCEU2020007, X. Hong), China Scholarship Council (fellowship to X. Hou), the European Union (ERC advanced grant no. 101021358 conferred to L.A.) and the DFG (Gottfried-Wilhelm-Leibniz-Preis attributed to L.A. and SPP 2363) are gratefully acknowledged. Calculations and ML trainings were performed on the high‐performance computing system at the Department of Chemistry, Zhejiang University.

Author information

Authors and Affiliations

  1. Center of Chemistry for Frontier Technologies, Department of Chemistry, State Key Laboratory of Clean Energy Utilization, Zhejiang University, Hangzhou, China

    Li-Cheng Xu, Shuo-Qing Zhang, Yan-Yu Li, Shu-Wen Li & Xin Hong

  2. Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Göttingen, Germany

    Johanna Frey, Xiaoyan Hou, João C. A. Oliveira & Lutz Ackermann

  3. Wöhler-Research Institute for Sustainable Chemistry (WISCh), Georg-August-Universität Göttingen, Göttingen, Germany

    Lutz Ackermann

  4. Beijing National Laboratory for Molecular Sciences, Beijing, China

    Xin Hong

  5. Key Laboratory of Precise Synthesis of Functional Molecules of Zhejiang Province, School of Science, Westlake University, Hangzhou, China

    Xin Hong

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Contributions

X. Hong and L.A. conceived and supervised the project. X. Hong and S.-Q.Z. designed the workflow of the ML. L.-C.X. and S.-W.L. performed the ML training and analysed the training data. J.F. and X. Hou performed the experiments and analysed the experimental data. Y.-Y.L. and J.C.A.O. performed the DFT calculations for the physical organic descriptors and the mechanistic studies. X. Hong. and L.A. wrote the manuscript with input from all the authors.

Corresponding authors

Correspondence to Lutz Ackermann or Xin Hong.

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Nature Synthesis thanks Tobias Gensch, Bartosz Grzybowski and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Peter Seavill, in collaboration with the Nature Synthesis team.

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Supplementary information

Supplementary Information

Machine learning and experimental details, Supplementary Figs. 1–37 and Tables 1–17.

Supplementary Data 1

Collected data of asymmetric pallada-electrocatalysed C–H activation

Source data

Source Data Fig. 4

Data for the three regression diagrams of Fig. 4a.

Source Data Fig. 5

Importance scores for top-5 features.

Source Data Fig. 6

Data for the regression diagram of Fig. 6e.

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Xu, LC., Frey, J., Hou, X. et al. Enantioselectivity prediction of pallada-electrocatalysed C–H activation using transition state knowledge in machine learning. Nat. Synth 2, 321–330 (2023). https://doi.org/10.1038/s44160-022-00233-y

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