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Thermodynamic control of asymmetric amplification in amino acid catalysis

Abstract

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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Acknowledgements

Funding from the EPSRC and AstraZeneca is gratefully acknowledged.

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Correspondence to Donna G. Blackmond.

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Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

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Supplementary Notes

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). https://doi.org/10.1038/nature04780

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