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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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/.
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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.
The authors declare no competing interests.
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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.
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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