Time-dependent enantiodivergent synthesis via sequential kinetic resolution

Abstract

The preparation of both enantiomers of chiral molecules is among the most fundamental tasks in organic synthesis, medicinal chemistry and materials science. Achieving this goal typically requires reversing the absolute configuration of the chiral component employed in the reaction system that is being used. The task becomes challenging when the natural source of the chiral component is not available in both configurations. Herein, we report a time-dependent enantiodivergent synthesis, in which an Ir-catalysed allylic substitution reaction uses one catalyst sequentially to promote two kinetic resolution reactions, enabling the synthesis of both enantiomers of the product using the same enantiomer of a chiral catalyst. The appropriate permutation of individual reaction rates is essential for the isolation of the chiral products in opposite configurations with high enantiopurity when quenched at different reaction times. This work provides an alternative solution for the preparation of both enantiomers of chiral molecules.

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Fig. 1: Synthesis of opposite enantiomers of chiral molecules.
Fig. 2: Discovery of time-dependent enantiodivergent synthesis.
Fig. 3: Mechanism of time-dependent enantiodivergent synthesis.

Data availability

All data generated or analysed during this study are included in the published Article and Supplementary Information. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 1917286 (5). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

Change history

  • 11 August 2020

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Acknowledgements

This paper is dedicated to H. N. C. Wong on the occasion of his 70th birthday. Financial support for this work was provided by the National Key R&D Program of China (2016YFA0202900), National Natural Science Foundation of China (21821002, 91856201) and Chinese Academy of Sciences (XDB20000000, QYZDY-SSW-SLH012). S.-L.Y. acknowledges the support from the Tencent Foundation through the XPLORER PRIZE.

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Contributions

H.-F.T. discovered the sequential KR reactions, optimized the conditions and evaluated the scope of the reaction; H.-F.T., P.Y. and C.Z. performed the mechanistic studies; and H.-F.T., P.Y. and Z.-H.L. conducted the derivation of the products. S.-L.Y. conceived and supervised the project. C.Z. wrote the manuscript with revisions suggested by all authors.

Corresponding author

Correspondence to Shu-Li You.

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Extended data

Extended Data Fig. 1 Time-dependent enantiodivergent synthesis via Ir-catalyzed asymmetric allylic substitution with 6-hydroxyisoquinoline.

a, Optimal results for the synthesis of both enantiomers of 3aa. b, The course of the e.e. value of 3aa over the reaction time. Reaction performed under Optimal conditions A.

Extended Data Fig. 2 Time-dependent enantiodivergent synthesis via Ir-catalyzed asymmetric allylic substitution with aniline.

a, Optimal results for the synthesis of both enantiomers of 9. b, The course of the e.e. value of 9 over the reaction time. Reaction conditions: aniline (0.2 mmol, 1.0 equiv.), (rac)-2a (2.0 equiv.), [Ir(cod)Cl]2 (1.5 mol%), (S)-L1 (6 mol%), 3,5-Cl2C6H3CO2H (10 mol%) in MeOH (0.1 M) at 40 °C.

Extended Data Fig. 3 Time-dependent enantiodivergent synthesis via Ir-catalyzed asymmetric allylic substitution with N-methyl aniline.

a, Optimal results for the synthesis of both enantiomers of 10. b, The course of the e.e. value of 10 over the reaction time. Reaction conditions: N-methyl aniline (0.1 mmol, 1.0 equiv.), (rac)-2a (2.0 equiv.), [Ir(cod)Cl]2 (1.5 mol%), (S)-L1 (6 mol%), 3,5-Cl2C6H3CO2H (10 mol%) in MeOH (0.1 M) at 40 °C.

Extended Data Fig. 4 Time-dependent enantiodivergent synthesis via Ir-catalyzed asymmetric allylic substitution with N-allyl aniline.

a, Optimal results for the synthesis of both enantiomers of 11. b, The course of the e.e. value of 11 over the reaction time. Reaction conditions: N-allyl aniline (0.2 mmol, 1.0 equiv.), (rac)-2a (2.0 equiv.), [Ir(cod)Cl]2 (1.5 mol%), (S)-L1 (6 mol%), 3,5-Cl2C6H3CO2H (10 mol%) in MeOH (0.1 M) at 40 °C.

Supplementary information

Supplementary Information

Details of optimizations of reaction conditions, product derivations, mechanistic studies and full characterization data of all new compounds. Supplementary Figs. 1–3 and Tables 1–9.

Supplementary Data 1

Crystallographic data for compound 5. CCDC reference 1917286.

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Tu, H., Yang, P., Lin, Z. et al. Time-dependent enantiodivergent synthesis via sequential kinetic resolution. Nat. Chem. 12, 838–844 (2020). https://doi.org/10.1038/s41557-020-0489-1

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