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.

  • Article
  • Published:

Demystifying the asymmetry-amplifying, autocatalytic behaviour of the Soai reaction through structural, mechanistic and computational studies

Abstract

The Soai reaction has profoundly impacted chemists’ perspective of autocatalysis, chiral symmetry breaking, absolute asymmetric synthesis and its role in the origin of biological homochirality. Here we describe the unprecedented observation of asymmetry-amplifying autocatalysis in the alkylation of 5-(trimethylsilylethynyl)pyridine-3-carbaldehyde using diisopropylzinc. Kinetic studies with a surrogate substrate and spectroscopic analysis of a series of zinc alkoxides that incorporate specific structural mutations reveal a ‘pyridine-assisted cube escape’. The new tetrameric cluster functions as a catalyst that activates the substrate through a two-point binding mode and poises a coordinated diisopropylzinc moiety for alkyl group transfer. Transition-state models leading to both the homochiral and heterochiral products were validated by density functional theory calculations. Moreover, experimental and computational analysis of the heterochiral complex provides a definitive explanation for the nonlinear behaviour of this system. Our deconstruction of the Soai system reveals the structural logic for autocatalyst evolution, function and substrate compatibility—a central mechanistic aspect of this iconic transformation.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Fig. 1: The Soai reaction system, current mechanistic understanding and salient contributions from this work.
Fig. 2: A new asymmetry-amplifying, autocatalytic pyridine system and a structure–activity relationship of the (auto)catalyst.
Fig. 3: Spectroscopic characterization of zinc alkoxides reveals structure-dependent solution-state aggregation.
Fig. 4: Diastereomeric species possible in a racemic cubic tetramer with their relative peak distributions.
Fig. 5: Structural logic for the evolution of the catalytically active, PyII SMS tetramer.
Fig. 6: Substrate constraints and kinetic studies for the enantioselective, positive nonlinear alkyl transfer activity of PyII.
Fig. 7: Catalysis by the PyII SMS tetramer and DFT studies for floor-to-floor substrate docking and alkyl transfer.
Fig. 8: Origin of nonlinearity in the amplifying, autocatalytic reaction.

Similar content being viewed by others

Data availability

All data mentioned in this manuscript are available as part of the main article or as Supplementary Information (Supplementary Figs. 1178 and Supplementary Tables 16). Initial rate kinetics data and DFT computation data are included in separate files.

References

  1. Soai, K., Shibata, T., Morioka, H. & Choji, K. Asymmetric autocatalysis and amplification of enantiomeric excess of a chiral molecule. Nature 378, 767–768 (1995).

    Article  CAS  Google Scholar 

  2. Soai, K., Kawasaki, T. & Matsumoto, A. Asymmetric autocatalysis of pyrimidyl alkanol and its application to the study on the origin of homochirality. Acc. Chem. Res. 47, 3643–3654 (2014).

    Article  CAS  Google Scholar 

  3. Sato, I., Urabe, H., Ishiguro, S., Shibata, T. & Soai, K. Amplification of chirality from extremely low to greater than 99.5% e.e. by asymmetric autocatalysis. Angew. Chem. Int. Ed. 42, 315–317 (2003).

    Article  CAS  Google Scholar 

  4. Soai, K. et al. Asymmetric synthesis of pyrimidyl alkanol without adding chiral substances by the addition of diisopropylzinc to pyrimidine-5-carbaldehyde in conjunction with asymmetric autocatalysis. Tetrahedron Asymmetry 14, 185–188 (2003).

    Article  CAS  Google Scholar 

  5. Singleton, D. A. & Vo, L. K. Enantioselective synthesis without discrete optically active additives. J. Am. Chem. Soc. 124, 10010–10011 (2002).

    Article  CAS  Google Scholar 

  6. Singleton, D. A. & Vo, L. K. A few molecules can control the enantiomeric outcome. Evidence supporting absolute asymmetric synthesis using the Soai asymmetric autocatalysis. Org. Lett. 5, 4337–4339 (2003).

    Article  CAS  Google Scholar 

  7. Soai, K., Shibata, T. & Kowata, Y. Production of optically active pyrimidylalkyl alcohol by spontaneous asymmetric synthesis. Japanese patent 1997 9-268179 (1996).

  8. Mislow, K. Absolute asymmetric synthesis: a commentary. Collect. Czech. Chem. Commun. 68, 849–864 (2003).

    Article  CAS  Google Scholar 

  9. Sato, I. et al. Highly enantioselective synthesis of organic compound using right- and left-handed helical silica. Tetrahedron Lett. 44, 721–724 (2003).

    Article  CAS  Google Scholar 

  10. Lutz, F., Sato, I. & Soai, K. The asymmetric power of chiral ligands determined by competitive asymmetric autocatalysis. Org. Lett. 6, 1613–1616 (2004).

    Article  CAS  Google Scholar 

  11. Kawasaki, T. et al. Highly enantioselective asymmetric autocatalysis using chiral ruthenium complex-ion-exchanged synthetic hectorite as a chiral initiator. Org. Biomol. Chem. 7, 1073–1075 (2009).

    Article  CAS  Google Scholar 

  12. Sato, I. et al. Determination of absolute configurations of amino acids by asymmetric autocatalysis of 2-alkynylpyrimidyl alkanol as a chiral sensor. J. Organomet. Chem. 692, 1783–1787 (2007).

    Article  CAS  Google Scholar 

  13. Kawasaki, T. et al. Asymmetric amplification using chiral cocrystals formed from achiral organic molecules by asymmetric autocatalysis. Angew. Chem. Int. Ed. 44, 2774–2777 (2005).

    Article  CAS  Google Scholar 

  14. Sato, I. et al. Asymmetric induction by helical hydrocarbons: [6]- and [5]Helicenes. Angew. Chem. Int. Ed. 40, 1096–1098 (2001).

    Article  CAS  Google Scholar 

  15. Kawasaki, T. et al. Chiral discrimination of cryptochiral saturated quaternary and tertiary hydrocarbons by asymmetric autocatalysis. J. Am. Chem. Soc. 128, 6032–6033 (2006).

    Article  CAS  Google Scholar 

  16. Kawasaki, T. et al. Enantioselective synthesis of near enantiopure compound by asymmetric autocatalysis triggered by asymmetric photolysis with circularly polarized light. J. Am. Chem. Soc. 127, 3274–3275 (2005).

    Article  CAS  Google Scholar 

  17. Kawasaki, T. et al. Autocatalysis triggered by carbon isotope (13C/12C) chirality. Science 324, 492–495 (2009).

    Article  CAS  Google Scholar 

  18. Kawasaki, T. et al. Asymmetric autocatalysis: triggered by chiral isotopomer arising from oxygen isotope substitution. Angew. Chem. Int. Ed. 50, 8131–8133 (2011).

    Article  CAS  Google Scholar 

  19. Matsumoto, A. et al. Asymmetric induction by a nitrogen 14N/15N isotopomer in conjunction with asymmetric autocatalysis. Angew. Chem. Int. Ed. 55, 15246–15249 (2016).

    Article  CAS  Google Scholar 

  20. Blackmond, D. G. The origin of biological homochirality. Cold Spring Harb. Perspect. Biol. 2, a002147 (2010).

    Article  Google Scholar 

  21. Flügel, R. M. Chirality and Life: A Short Introduction to the Early Phases of Chemical Evolution 1st edn (Springer, 2011).

  22. Weissbuch, I. & Lahav, M. Crystalline architectures as templates of relevance to the origins of homochirality. Chem. Rev. 111, 3236–3267 (2011).

    Article  CAS  Google Scholar 

  23. Cintas, P. (ed.) Biochirality: Origins, Evolution and Molecular Recognition 1st edn (Topics in Current Chemistry, Springer-Verlag, 2013).

  24. Frank, F. On spontaneous asymmetric synthesis. Biochim. Biophys. Acta 11, 459–463 (1953).

    Article  CAS  Google Scholar 

  25. Blackmond, D. G., McMillan, C. R., Ramdeehul, S., Schorm, A. & Brown, J. M. Origins of asymmetric amplification in autocatalytic alkylzinc additions. J. Am. Chem. Soc. 123, 10103–10104 (2001).

    Article  CAS  Google Scholar 

  26. Buono, F. G. & Blackmond, D. G. Kinetic evidence for a tetrameric transition state in the asymmetric autocatalytic alkylation of pyrimidyl aldehydes. J. Am. Chem. Soc. 125, 8978–8979 (2003).

    Article  CAS  Google Scholar 

  27. Sato, I. et al. Relationship between the time, yield, and enantiomeric excess of asymmetric autocatalysis of chiral 2-alkynyl-5-pyrimidyl alkanol with amplification of enantiomeric excess. Tetrahedron Asymmetry 14, 975–979 (2003).

    Article  CAS  Google Scholar 

  28. Gridnev, I. D., Serafimov, J. M. & Brown, J. M. Solution structure and reagent binding of the zinc alkoxide catalyst in the Soai asymmetric autocatalytic reaction. Angew. Chem. Int. Ed. 43, 4884–4887 (2004).

    Article  CAS  Google Scholar 

  29. Islas, J. R. et al. Mirror-symmetry breaking in the Soai reaction: a kinetic understanding. Proc. Natl Acad. Sci. USA 102, 13743–13748 (2005).

    Article  CAS  Google Scholar 

  30. Schiaffino, L. & Ercolani, G. Unraveling the mechanism of the Soai asymmetric autocatalytic reaction by first-principles calculations: induction and amplification of chirality by self-assembly of hexamolecular complexes. Angew. Chem. Int. Ed. 47, 6832–6835 (2008).

    Article  CAS  Google Scholar 

  31. Ercolani, G. & Schiaffino, L. Putting the mechanism of the Soai reaction to the test: DFT study of the role of aldehyde and dialkylzinc structure. J. Org. Chem. 76, 2619–2626 (2011).

    Article  CAS  Google Scholar 

  32. Buhse, T., Noble-Terán, M. E., Cruz, J.-M., Micheau, J.-C. & Coudret, C. in Advances in Asymmetric Autocatalysis and Related Topics (eds Pályi, G. et al.) 71–110 (Academic Press, 2017).

  33. Klankermayer, J., Gridnev, I. D. & Brown, J. M. Role of the isopropyl group in asymmetric autocatalytic zinc alkylations. Chem. Commun. 3151–3153 (2007).

  34. Quaranta, M., Gehring, T., Odell, B., Brown, J. M. & Blackmond, D. G. Unusual inverse temperature dependence on reaction rate in the asymmetric autocatalytic alkylation of pyrimidyl aldehydes. J. Am. Chem. Soc. 132, 15104–15107 (2010).

    Article  CAS  Google Scholar 

  35. Gridnev, I. D. & Vorobiev, A. Kh Quantification of sophisticated equilibria in the reaction pool and amplifying catalytic cycle of the Soai reaction. ACS Catal. 2, 2137–2149 (2012).

    Article  CAS  Google Scholar 

  36. Matsumoto, A. et al. Crystal structure of the isopropylzinc alkoxide of pyrimidyl alkanol: mechanistic insights for asymmetric autocatalysis with amplification of enantiomeric excess. Angew. Chem. Int. Ed. 54, 15218–15221 (2015).

    Article  CAS  Google Scholar 

  37. Gehring, T., Busch, M., Schlageter, M. & Weingand, D. A concise summary of experimental facts about the Soai reaction. Chirality 22, E173–E182 (2010).

    Article  CAS  Google Scholar 

  38. Shibata, T., Yonekubo, S. & Soai, K. Practically perfect asymmetric autocatalysis with (2-alkynyl-5-pyrimidyl)alkanols. Angew. Chem. Int. Ed. 38, 659–661 (1999).

    Article  CAS  Google Scholar 

  39. Tanji, S. et al. Asymmetric autocatalysis of 5-carbamoyl-3-pyridyl alkanols with amplification of enantiomeric excess. Tetrahedron Asymmetry 11, 4249–4253 (2000).

    Article  CAS  Google Scholar 

  40. Shibata, T., Choji, K., Hayase, T., Aizu, Y. & Soai, K. Asymmetric autocatalytic reaction of 3-quinolylalkanol with amplification of enantiomeric excess. Chem. Commun. 1235–1236 (1996).

  41. Soai, K., Niwa, S. & Hori, H. Asymmetric self-catalytic reaction. Self-production of chiral 1-(3-pyridyl)alkanols as chiral self-catalysts in the enantioselective addition of dialkylzinc reagents to pyridine-3-carbaldehyde. J. Chem. Soc. Chem. Commun. 982–983 (1990).

  42. Brown, J. M., Gridnev, I. & Klankermayer, J. in Amplification of Chirality (ed Soai, K.) 35–65 (Springer, 2008).

  43. Romagnoli, C., Sieng, B. & Amedjkouh, M. Asymmetric amplification coupling enantioselective autocatalysis and asymmetric induction for alkylation of azaaryl aldehydes. Eur. J. Org. Chem. 2015, 4087–4092 (2015).

    Article  CAS  Google Scholar 

  44. Noltes, J. G. & Boersma, J. Investigations on organozinc compounds IX. Coordination chemistry of organozinc compounds RZnX: organozinc derivatives of tert-butanol, some phenols, diethylhydroxylamine and some oximes. J. Organomet. Chem. 12, 425–431 (1968).

    Article  CAS  Google Scholar 

  45. Jana, S., Berger, R. J. F., Fröhlich, R., Pape, T. & Mitzel, N. W. Oxygenation of simple zinc alkyls: surprising dependence of product distributions on the alkyl substituents and the presence of water. Inorg. Chem. 46, 4293–4297 (2007).

    Article  CAS  Google Scholar 

  46. Kitamura, M., Okada, S., Suga, S. & Noyori, R. Enantioselective addition of dialkylzincs to aldehydes promoted by chiral amino alcohols. Mechanism and nonlinear effect. J. Am. Chem. Soc. 111, 4028–4036 (1989).

    Article  CAS  Google Scholar 

  47. Blackmond, D. G. Autocatalytic models for the origin of biological homochirality. Chem. Rev. https://doi.org/10.1021/acs.chemrev.9b00557 (2019).

Download references

Acknowledgements

We are grateful for generous financial support from the University of Illinois. S.V.A. is grateful to the University of Illinois for Graduate Fellowships. A.S. acknowledges support from a NIH Chemistry–Biology Interface Research Training Grant (T32GM008496). We are also grateful for the support services of the NMR, mass spectrometry and microanalytical laboratories of the University of Illinois at Urbana-Champaign.

Author information

Authors and Affiliations

Authors

Contributions

S.V.A. conceptualized the project, designed and performed chemistry experiments, analysed data and wrote the manuscript. S.E.D. secured funding, supervised, analysed data and revised the manuscript. A.S. performed DFT calculations under the supervision of K.N.H. All authors contributed in assembling the final draft of the manuscript.

Corresponding author

Correspondence to Scott E. Denmark.

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.

Supplementary information

Supplementary Information

Complete experimental details, synthesis, spectroscopic characterizations, kinetics, computational studies and miscellaneous supporting data. Includes Supplementary Figs. 1–177 and Tables 1–6.

Data Tables for Initial Rate Experiments

Raw and processed data obtained from in situ infrared monitoring of aldehyde consumption in initial rate studies.

Data Tables for Cartesian Coordinates and Energies from DFT studies

Coordinates and energies for all DFT calculated structures.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Athavale, S., Simon, A., Houk, K.N. et al. Demystifying the asymmetry-amplifying, autocatalytic behaviour of the Soai reaction through structural, mechanistic and computational studies. Nat. Chem. 12, 412–423 (2020). https://doi.org/10.1038/s41557-020-0421-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41557-020-0421-8

This article is cited by

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