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Catalytic deracemization of chiral allenes by sensitized excitation with visible light

Naturevolume 564pages240243 (2018) | Download Citation

Abstract

Chiral compounds exist as enantiomers that are non-superimposable mirror images of each other. Owing to the importance of enantiomerically pure chiral compounds1—for example, as active pharmaceutical ingredients—separation of racemates (1:1 mixtures of enantiomers) is extensively performed2. Frequently, however, only a single enantiomeric form of a chiral compound is required, which raises the question of how a racemate can be selectively converted into a single enantiomer. Such a deracemization3 process is entropically disfavoured and cannot be performed by a conventional catalyst in solution. Here we show that it is possible to photochemically deracemize chiral compounds with high enantioselectivity using irradiation with visible light (wavelength of 420 nanometres) in the presence of catalytic quantities (2.5 mole per cent) of a chiral sensitizer. We converted an array of 17 chiral racemic allenes into the respective single enantiomers with 89 to 97 per cent enantiomeric excess. The sensitizer is postulated to operate by triplet energy transfer to the allene, with different energy-transfer efficiencies for the two enantiomers. It thus serves as a unidirectional catalyst that converts one enantiomer but not the other, and the decrease in entropy is compensated by light energy. Photochemical deracemization enables the direct formation of enantiopure materials from a racemic mixture of the same compound, providing a novel approach to the challenge of creating asymmetry.

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The findings of this study are available within the paper and its Supplementary Information.

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References

  1. 1.

    Carreira, E. M. & Yamamoto, H. (eds) Comprehensive Chirality (Academic Press, Amsterdam, 2012).

  2. 2.

    Lorenz, H. & Seidel-Morgenstern, A. Processes to separate enantiomers. Angew. Chem. 53, 1218–1250 (2014).

  3. 3.

    Palmans, A. R. A. Deracemisations under kinetic and thermodynamic control. Mol. Syst. Des. Eng. 2, 34–46 (2017).

  4. 4.

    Rachwalski, M., Vermue, N. & Rutjes, F. P. J. T. Recent advances in enzymatic and chemical deracemisation of racemic compounds. Chem. Soc. Rev. 42, 9268–9282 (2013).

  5. 5.

    Inoue, Y., Yokoyama, T., Yamasaki, N. & Tai, A. An optical yield that increases with temperature in a photochemically induced enantiomeric isomerization. Nature 341, 225–226 (1989); erratum 342, 958 (1989).

  6. 6.

    Maeda, R. et al. Planar-to-planar chirality transfer in the excited state. Enantiodifferentiating photoisomerization of cyclooctenes sensitized by planar-chiral paracyclophane. J. Am. Chem. Soc. 133, 10379–10381 (2011).

  7. 7.

    Rodriguez, O. & Morrison, H. Photosensitized racemization of an optically active allene. J. Chem. Soc. D 679 (1971).

  8. 8.

    Bucher, G., Mahajan, A. A. & Schmittel, M. The photochemical C2–C6 cyclization of enyne–allenes: interception of the fulvene diradical with a radical clock ring opening. J. Org. Chem. 74, 5850–5860 (2009).

  9. 9.

    Drucker, C. S., Toscano, V. G. & Weiss, R. G. A general method for the determination of steric effects during collisional energy transfer. Partial photoresolution of penta-2,3-diene. J. Am. Chem. Soc. 95, 6482–6484 (1973).

  10. 10.

    Alonso, R. & Bach, T. A chiral thioxanthone as organocatalyst for enantioselective [2+2] photocycloaddition reactions induced by visible light. Angew. Chem. 53, 4368–4371 (2014).

  11. 11.

    Gotthardt, H. & Hammond, G. S. Zur Photochemie des Allens. Chem. Ber. 108, 657–663 (1975).

  12. 12.

    Shepard, M. S. & Carreira, E. M. Asymmetric photocycloadditions with an optically active allenylsilane: trimethylsilyl as a removable stereocontrolling group for the enantioselective synthesis of exo-methylenecyclobutanes. J. Am. Chem. Soc. 119, 2597–2605 (1997).

  13. 13.

    Fielding, L. Determination of association constants (K a) from solution NMR data. Tetrahedron 56, 6151–6170 (2000).

  14. 14.

    Dexter, D. L. A theory of sensitized luminescence in solids. J. Chem. Phys. 21, 836–850 (1953).

  15. 15.

    Turro, N. J., Ramamurthy, V. & Scaiano, J. C. Modern Molecular Photochemistry of Organic Compounds 411–413 (University Science Books, Sausalito, 2010).

  16. 16.

    Brennan, C. M., Caldwell, R. A., Elbert, J. E. & Unett, D. J. Nonvertical triplet excitation transfer to arylalkene acceptors: further evidence that double bond torsion is unimportant. J. Am. Chem. Soc. 116, 3460–3464 (1994).

  17. 17.

    Silvi, M. & Melchiorre, P. Enhancing the potential of enantioselective organocatalysis with light. Nature 554, 41–49 (2018).

  18. 18.

    Stephenson, C. R. J., Yoon, T. P. & MacMillan, D. W. C. (eds) Visible Light Photocatalysis in Organic Chemistry (Wiley-VCH, Weinheim, 2018).

  19. 19.

    Brimioulle, R., Lenhart, D., Maturi, M. M. & Bach, T. Enantioselective catalysis of photochemical reactions. Angew. Chem. 54, 3872–3890 (2015).

  20. 20.

    Meierhenrich, U. Amino Acids and the Asymmetry of Life (Springer, Berlin, 2008)

  21. 21.

    Hammond, G. S. & Cole, R. S. Asymmetric induction during energy transfer. J. Am. Chem. Soc. 87, 3256–3257 (1965).

  22. 22.

    Ouannès, C., Beugelmans, R. & Roussi, G. Asymmetric induction during transfer of triplet energy. J. Am. Chem. Soc. 95, 8472–8474 (1973).

  23. 23.

    Balavoine, G., Jugé, S. & Kagan, H. B. Photoactivation optique du methyl p-tolyl sulfoxyde racemique par emploi d’un sensibilisateur chiral. Tetrahedr. Lett. 14, 4159–4162 (1973).

  24. 24.

    Poplata, S. & Bach, T. Enantioselective intermolecular [2+2] photocycloaddition reaction of cyclic enones and its application in a synthesis of (−)-grandisol. J. Am. Chem. Soc. 140, 3228–3231 (2018).

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Acknowledgements

Financial support by the Deutsche Forschungsgemeinschaft (DFG) via grant Ba1372/20 and GRK 1626 (T.B.) and through the Cluster of Excellence (EXC 1069) RESOLV project (S.M.H.) is acknowledged. A.H.-H. thanks the research training group (Graduiertenkolleg GRK) 1626 ‘Chemical Photocatalysis’ for a scholarship. A.V.S. acknowledges the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) for a post-doctoral research fellowship (BEX number 10744/13-4). C.B. is grateful to S. Grimme for discussions and for admission to computing clusters. We thank O. Ackermann and J. Kudermann for help with the high-performance liquid chromatography and gas–liquid chromatography analyses, A. Strauch for help with the circular dichroism measurements and A. Tröster for compounds for experimental comparison.

Reviewer information

Nature thanks Y. Inoue and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Affiliations

  1. Department Chemie and Catalysis Research Center (CRC), Technische Universität München, Garching, Germany

    • Alena Hölzl-Hobmeier
    • , Andreas Bauer
    • , Alexandre Vieira Silva
    •  & Thorsten Bach
  2. Fakultät für Chemie und Biochemie, Ruhr-Universität Bochum, Bochum, Germany

    • Stefan M. Huber
  3. Mulliken Center for Theoretical Chemistry, Institut für Physikalische und Theoretische Chemie, Universität Bonn, Bonn, Germany

    • Christoph Bannwarth

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Contributions

A.H.-H., A.B. and A.V.S. performed and analysed the experiments. A.H.-H., A.B., A.V.S. and T.B. designed the experiments. A.H.-H., A.B. and T.B. prepared the manuscript. S.M.H. performed all DFT calculations related to complexes 2·ent-1a and 2·1a. C.B. computed the theoretical chiroptical data for compound 1a.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Thorsten Bach.

Supplementary information

  1. Supplementary Information

    This file contains: General Information; Analytical Methods; Synthetic Procedures and Analytical Data; Optimisation of Irradiation Conditions; Determination of the Absolute Configuration; Details for the DFT Investigations; NMR Spectra; NMR-Titration; Determination of Quantum Yield; Emission Spectra of Catalyst 2; Estimation of Allene Triplet Energy; HPLC Traces; and References.

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https://doi.org/10.1038/s41586-018-0755-1

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