Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Time-dependent enantiodivergent synthesis via sequential kinetic resolution

Nature Chemistry volume 12, pages 838–844 (2020)Cite this article

Subjects

A Publisher Correction to this article was published on 11 August 2020

This article has been updated

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

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

References

  1. Ariëns, E. J. Stereochemistry, a basis for sophisticated nonsense in pharmacokinetics and clinical pharmacology. Eur. J. Clin. Pharmacol. 26, 663–668 (1984).

    Article  Google Scholar 

  2. McConathy, J. & Owens, M. J. Stereochemistry in drug action. Prim. Care Companion J. Clin. Psychiatry 5, 70–73 (2003).

    Article  Google Scholar 

  3. Carreira, E. M. & Yamamoto, H. (eds) Comprehensive Chirality (Elsevier, 2012).

  4. Wang, Y., Xu, J., Wang, Y. & Chen, H. Emerging chirality in nanoscience. Chem. Soc. Rev. 42, 2930–2962 (2013).

    Article  CAS  Google Scholar 

  5. Liu, M., Zhang, L. & Wang, T. Supramolecular chirality in self-assembled systems. Chem. Rev. 115, 7304–7397 (2015).

    Article  CAS  Google Scholar 

  6. Brill, Z. G., Condakes, M. L., Ting, C. P. & Maimone, T. J. Navigating the chiral pool in the total synthesis of complex terpene natural products. Chem. Rev. 117, 11753–11795 (2017).

    Article  CAS  Google Scholar 

  7. Gnas, Y. & Glorius, F. Chiral auxiliaries – principles and recent applications. Synthesis 2006, 1899–1930 (2006).

    Article  Google Scholar 

  8. Paquette, L. A. (ed.) Handbook of Reagents for Organic Synthesis: Chiral Reagents for Asymmetric Synthesis (Wiley, 2003).

  9. Jacobsen, E. N., Pfaltz, A. & Yamamoto, H. (eds) Comprehensive Asymmetric Catalysis (Springer, 1999).

  10. Yoon, T. P. & Jacobsen, E. N. Privileged chiral catalysts. Science 299, 1691–1693 (2003).

    Article  CAS  Google Scholar 

  11. Zhou, Q.-L. (ed.) Privileged Chiral Ligands and Catalysts (Wiley, 2011).

  12. Blaser, H.-U. & Schmidt, E. (eds) Asymmetric Catalysis on Industrial Scale: Challenges, Approaches and Solutions (Wiley, 2004).

  13. Krautwald, S., Sarlah, D., Schafroth, M. A. & Carreira, E. M. Enantio- and diastereodivergent dual catalysis: α-allylation of branched aldehydes. Science 340, 1065–1068 (2013).

    Article  CAS  Google Scholar 

  14. Oliveira, M. T., Luparia, M., Audisio, D. & Maulide, N. Dual catalysis becomes diastereodivergent. Angew. Chem. Int. Ed. 52, 13149–13152 (2013).

    Article  CAS  Google Scholar 

  15. Shi, S.-L., Wong, Z. L. & Buchwald, S. L. Copper-catalysed enantioselective stereodivergent synthesis of amino alcohols. Nature 532, 353–356 (2016).

    Article  CAS  Google Scholar 

  16. Krautwald, S. & Carreira, E. M. Stereodivergence in asymmetric catalysis. J. Am. Chem. Soc. 139, 5627–5639 (2017).

    Article  CAS  Google Scholar 

  17. Sibi, M. P. & Liu, M. Reversal of stereochemistry in enantioselective transformations. Can they be planned or are they just accidental? Curr. Org. Chem. 5, 719–755 (2001).

    Article  CAS  Google Scholar 

  18. Bartók, M. Unexpected inversions in asymmetric reactions: reactions with chiral metal complexes, chiral organocatalysts, and heterogeneous chiral catalysts. Chem. Rev. 110, 1663–1705 (2010).

    Article  Google Scholar 

  19. Beletskaya, I. P., Nájera, C. & Yus, M. Stereodivergent catalysis. Chem. Rev. 118, 5080–5200 (2018).

    Article  CAS  Google Scholar 

  20. Yamaguchi, S., Mosher, H. S. & Pohland, A. Reversal in stereoselectivity depending upon the age of a chiral lithium alkoxyaluminohydride reducing reagent. J. Am. Chem. Soc. 94, 9254–9255 (1972).

    Article  CAS  Google Scholar 

  21. Zhou, J. & Tang, Y. Enantioselective Friedel–Crafts reaction of indoles with arylidene malonates catalyzed by iPr-bisoxazoline-Cu(OTf)2. Chem. Commun. 432–433 (2004).

  22. Trost, B. M., Fettes, A. & Shireman, B. T. Direct catalytic asymmetric aldol additions of methyl ynones. Spontaneous reversal in the sense of enantioinduction. J. Am. Chem. Soc. 126, 2660–2661 (2004).

    Article  CAS  Google Scholar 

  23. Kagan, H. B. & Fiaud, J. C. Kinetic resolution. Top. Stereochem. 18, 249–330 (1988).

    CAS  Google Scholar 

  24. Keith, J. M., Larrow, J. F. & Jacobsen, E. N. Practical considerations in kinetic resolution reactions. Adv. Synth. Catal. 343, 5–26 (2001).

    Article  CAS  Google Scholar 

  25. Vedejs, E. & Jure, M. Efficiency in nonenzymatic kinetic resolution. Angew. Chem. Int. Ed. 44, 3974–4001 (2005).

    Article  CAS  Google Scholar 

  26. Bhat, V., Welin, E. R., Guo, X. & Stoltz, B. M. Advances in stereoconvergent catalysis from 2005 to 2015: transition-metal-mediated stereoablative reactions, dynamic kinetic resolutions, and dynamic kinetic asymmetric transformations. Chem. Rev. 117, 4528–4561 (2017).

    Article  CAS  Google Scholar 

  27. Vedejs, E. & Chen, X. Parallel kinetic resolution. J. Am. Chem. Soc. 119, 2584–2585 (1997).

    Article  CAS  Google Scholar 

  28. Wu, B., Parquette, J. R. & RajanBabu, T. V. Regiodivergent ring opening of chiral aziridines. Science 326, 1662 (2009).

    Article  CAS  Google Scholar 

  29. Miller, L. C. & Sarpong, R. Divergent reactions on racemic mixtures. Chem. Soc. Rev. 40, 4550–4562 (2011).

    Article  CAS  Google Scholar 

  30. Kreituss, I. & Bode, J. W. Flow chemistry and polymer-supported pseudoenantiomeric acylating agents enable parallel kinetic resolution of chiral saturated N-heterocycles. Nature Chem. 9, 446–452 (2017).

    Article  CAS  Google Scholar 

  31. Pape, A. R., Kaliappan, K. P. & Kündig, E. P. Transition-metal-mediated dearomatization reactions. Chem. Rev. 100, 2917–2940 (2000).

    Article  CAS  Google Scholar 

  32. Roche, S. P. & Porco, J. A. Jr. Dearomatization strategies in the synthesis of complex natural products. Angew. Chem. Int. Ed. 50, 4068–4093 (2011).

    Article  CAS  Google Scholar 

  33. Zhuo, C.-X., Zhang, W. & You, S.-L. Catalytic asymmetric dearomatization reactions. Angew. Chem. Int. Ed. 51, 12662–12686 (2012).

    Article  Google Scholar 

  34. Zhuo, C.-X., Zheng, C. & You, S.-L. Transition-metal-catalyzed asymmetric allylic dearomatization reactions. Acc. Chem. Res. 47, 2558–2573 (2014).

    Article  CAS  Google Scholar 

  35. Zheng, C. & You, S.-L. Catalytic asymmetric dearomatization by transition-metal catalysis: a method for transformations of aromatic compounds. Chem 1, 830–857 (2016).

    Article  CAS  Google Scholar 

  36. Yang, Z.-P., Jiang, R., Zheng, C. & You, S.-L. Iridium-catalyzed intramolecular asymmetric allylic alkylation of hydroxyquinolines: simultaneous weakening of the aromaticity of two consecutive aromatic rings. J. Am. Chem. Soc. 140, 3114–3119 (2018).

    Article  CAS  Google Scholar 

  37. Trost, B. M. & Crawley, M. L. Asymmetric transition-metal-catalyzed allylic alkylations: applications in total synthesis. Chem. Rev. 103, 2921–2944 (2003).

    Article  CAS  Google Scholar 

  38. Lu, Z. & Ma, S. Metal-catalyzed enantioselective allylation in asymmetric synthesis. Angew. Chem. Int. Ed. 47, 258–297 (2008).

    Article  CAS  Google Scholar 

  39. Cheng, Q. et al. Iridium-catalyzed asymmetric allylic substitution reactions. Chem. Rev. 119, 1855–1969 (2019).

    Article  CAS  Google Scholar 

  40. Zhao, X., Liu, D., Guo, H., Liu, Y. & Zhang, W. C–N bond cleavage of allylic amines via hydrogen bond activation with alcohol solvents in Pd-catalyzed allylic alkylation of carbonyl compounds. J. Am. Chem. Soc. 133, 19354–19357 (2011).

    Article  CAS  Google Scholar 

  41. Schreiber, S. L., Schreiber, T. S. & Smith, D. B. Reactions that proceed with a combination of enantiotopic group and diastereotopic face selectivity can deliver products with very high enantiomeric excess: experimental support of a mathematical model. J. Am. Chem. Soc. 109, 1525–1529 (1987).

    Article  CAS  Google Scholar 

  42. Rakels, J. L. L., Wolff, A., Straathof, A. J. J. & Heijnen, J. J. Sequential kinetic resolution by two enantioselective enzymes. Biocatalysis 9, 31–47 (1994).

    Article  CAS  Google Scholar 

  43. Kroutil, W., Kleewein, A. & Faber, K. A computer program for analysis, simulation and optimization of asymmetric catalytic processes proceeding through two consecutive steps. Type 2: sequential kinetic resolutions. Tetrahedron Asymmetry 8, 3263–3274 (1997).

    Article  CAS  Google Scholar 

  44. Elenkov, M. M., Tang, L., Hauer, B. & Janssen, D. B. Sequential kinetic resolution catalyzed by halohydrin dehalogenase. Org. Lett. 8, 4227–4229 (2006).

    Article  Google Scholar 

  45. Harrer, S., Greenhalgh, M. D., Neyyappadath, R. M. & Smith, A. D. Isothiourea-catalysed sequential kinetic resolution of acyclic (±)-1,2-diols. Synlett 30, 1555–1560 (2019).

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China

    Hang-Fei Tu, Pusu Yang, Zi-Hua Lin, Chao Zheng & Shu-Li You

Authors
  1. Hang-Fei Tu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pusu Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zi-Hua Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chao Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shu-Li You
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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.

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tu, HF., Yang, P., Lin, ZH. 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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41557-020-0489-1

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing