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Thermodynamic control of asymmetric amplification in amino acid catalysis


Ever since Pasteur noticed that tartrate crystals exist in two non-superimposable forms that are mirror images of one another—as are left and right hands—the phenomenon of chirality has intrigued scientists. On the molecular level, chirality often has a profound impact on recognition and interaction events and is thus important to biochemistry and pharmacology. In chemical synthesis, much effort has been directed towards developing asymmetric synthesis strategies that yield product molecules with a significant excess of either the left-handed or right-handed enantiomer. This is usually achieved by making use of chiral auxiliaries or catalysts that influence the course of a reaction, with the enantiomeric excess (ee) of the product linearly related to the ee of the auxiliary or catalyst used. In recent years, however, an increasing number of asymmetric reactions have been documented where this relationship is nonlinear1, an effect that can lead to asymmetric amplification. Theoretical models2,3 have long suggested that autocatalytic processes can result in kinetically controlled asymmetric amplification, a prediction that has now been verified experimentally4,5,6 and rationalized mechanistically7,8,9,10,11,12,13,14 for an autocatalytic alkylation reaction. Here we show an alternative mechanism that gives rise to asymmetric amplification based on the equilibrium solid-liquid phase behaviour of amino acids in solution. This amplification mechanism is robust and can operate in aqueous systems, making it an appealing proposition for explaining one of the most tantalizing examples of asymmetric amplification—the development of high enantiomeric excess in biomolecules from a presumably racemic prebiotic world.

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Figure 1: Reaction and solution behaviour as a function of the overall proline enantiomeric excess.
Figure 2: Ternary phase diagram of d -proline, l -proline and DMSO at 25 °C.
Figure 3: Nonlinear effects in an amino-acid mediated aldol reaction.

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  1. Girard, C. & Kagan, H. B. Nonlinear effects in asymmetric synthesis and stereoselective reactions: ten years of investigation. Angew. Chem. Int. Edn 37, 2923–2959 (1998)

    Article  CAS  Google Scholar 

  2. Frank, F. C. Spontaneous asymmetric synthesis. Biochim. Biophys. Acta 11, 459–463 (1953)

    Article  CAS  Google Scholar 

  3. Calvin, M. Molecular Evolution (Oxford Univ. Press, Oxford, UK, 1969)

    Google Scholar 

  4. Shibata, T., Morioka, H., Hayase, T., Choji, K. & Soai, K. Highly enantioselective catalytic asymmetric automultiplication of chiral pyrimidyl alcohol. J. Am. Chem. Soc. 118, 471–472 (1996)

    Article  CAS  Google Scholar 

  5. 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)

  6. 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  ADS  Google Scholar 

  7. 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 

  8. Blackmond, D. G. Description of the condition for asymmetric amplification in autocatalytic reactions. Adv. Synth. Catal. 344, 156–158 (2002)

    Article  CAS  Google Scholar 

  9. 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 

  10. Buono, F. G., Iwamura, H. & Blackmond, D. G. Physical and chemical rationalization for asymmetric amplification in autocatalytic reactions. Angew. Chem. Int. Edn 43, 2099–2103 (2004)

    Article  CAS  Google Scholar 

  11. Blackmond, D. G. Asymmetric autocatalysis and its implications for the origin of homochirality. Proc. Natl. Acad. Sci. USA 101, 5732–5736 (2004)

    Article  CAS  ADS  Google Scholar 

  12. Gridnev, I. D. & Brown, J. M. Asymmetric autocatalysis: novel structures, novel mechanism? Proc. Natl. Acad. Sci. USA 101, 5727–5731 (2004)

    Article  CAS  ADS  Google Scholar 

  13. 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. Edn 43, 4884–4887 (2004)

    Article  CAS  Google Scholar 

  14. Gridnev, I. D., Serafimov, J. M., Quiney, H. & Brown, J. M. Reflections on spontaneous asymmetric synthesis by amplifying autocatalysis. Org. Biomol. Chem. 1, 3811–3819 (2003)

    Article  CAS  Google Scholar 

  15. Mathew, S. P., Iwamura, H. & Blackmond, D. G. Amplification of enantiomeric excess in a proline-mediated reaction. Angew. Chem. Int. Edn 43, 3317–3321 (2004)

    Article  CAS  Google Scholar 

  16. Iwamura, H., Mathew, S. P. & Blackmond, D. G. In situ catalyst improvement in the proline-mediated α-amination of aldehydes. J. Am. Chem. Soc. 126, 11770–11771 (2004)

    Article  CAS  Google Scholar 

  17. Hoang, L., Bahmanyar, S., Houk, K. N. & List, B. Kinetic and stereochemical evidence for the involvement of only one proline molecule in the transition states of proline-catalyzed intra- and intermolecular aldol reactions. J. Am. Chem. Soc. 125, 16–17 (2003)

    Article  CAS  Google Scholar 

  18. Agami, C. Mechanism of the proline-catalyzed enantioselective aldol reaction. Recent advances. Bull. Soc. Chim. Fr.(3), 499–507 (1988)

  19. Blackmond, D. G. Kinetic aspects of nonlinear effects in asymmetric catalysis. Acc. Chem. Res. 33, 402–411 (2000)

    Article  CAS  Google Scholar 

  20. Roozeboom, H. W. B. Solubility and melting-point as criteria for racemate compounds, pseudoracemic mix-crystals and inactive conglomerates. Z. Phys. Chem. Stoechiometrie Verwandtschaftslehre 28, 494–517 (1899)

    CAS  Google Scholar 

  21. Jacques, J., Collet, A. & Wilen, S. H. Enantiomers, Racemates and Resolution Ch. 3 (John Wiley, New York, 1981)

    Google Scholar 

  22. Rodrigo, A. A., Lorenz, H. & Seidel-Morgenstern, A. Online monitoring of preferential crystallization of enantiomers. Chirality 16, 499–508 (2004)

    Article  CAS  Google Scholar 

  23. Podlech, J. Origin of organic molecules and biomolecular homochirality. Cell. Mol. Life Sci. 58, 44–60 (2001)

    Article  CAS  Google Scholar 

  24. Cordova, A. et al. Acyclic amino acid-catalyzed direct asymmetric aldol reactions: alanine, the simplest stereoselective organocatalyst. Chem. Commun. 3586 (2005)

  25. Borsenberger, V. et al. Exploratory studies to investigate a linked prebiotic origin of RNA and coded peptides. Chem. Biodivers. 1, 203–246 (2004)

    Article  CAS  Google Scholar 

  26. Takats, Z., Nanita, S. C. & Cooks, R. G. Serine octamer reactions: indicators of prebiotic relevance. Angew. Chem. Int. Edn 42, 3521–3523 (2003)

    Article  CAS  Google Scholar 

  27. Morowitz, H. J. A mechanism for the amplification of fluctuations in racemic mixtures. J. Theor. Biol 25, 491 (1969)

    Article  CAS  Google Scholar 

  28. Welch, C. J. Formation of highly enantioenriched microenvironments by stochastic sorting of conglomerate crystals: a plausible mechanism for generation of enantioenrichment on the prebiotic earth. Chirality 13, 425–427 (2001)

    Article  CAS  Google Scholar 

  29. Kondepudi, D. K. & Asakura, K. Chiral autocatalysis, spontaneous symmetry breaking, and stochastic behavior. Acc. Chem. Res. 34, 946–954 (2001)

    Article  CAS  Google Scholar 

  30. Kondepudi, D. K., Kaufman, R. J. & Singh, N. Chiral symmetry breaking in sodium chlorate crystallization. Science 250, 975–977 (1990)

    Article  CAS  ADS  Google Scholar 

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Funding from the EPSRC and AstraZeneca is gratefully acknowledged.

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Correspondence to Donna G. Blackmond.

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This file contains Supplementary Methods, Supplementary Tables 1–5, Supplementary Figures 1 and 2 and Supplementary Equations 1 and 2. (PDF 101 kb)

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Klussmann, M., Iwamura, H., Mathew, S. et al. Thermodynamic control of asymmetric amplification in amino acid catalysis. Nature 441, 621–623 (2006).

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