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Scaleable catalytic asymmetric Strecker syntheses of unnatural α-amino acids

Nature volume 461, pages 968–970 (2009)Cite this article

Abstract

α-Amino acids are the building blocks of proteins and are widely used as components of medicinally active molecules and chiral catalysts1,2,3,4,5. Efficient chemo-enzymatic methods for the synthesis of enantioenriched α-amino acids have been developed, but it is still a challenge to obtain non-natural amino acids6,7. Alkene hydrogenation is broadly useful for the enantioselective catalytic synthesis of many classes of amino acids8,9, but it is not possible to obtain α-amino acids bearing aryl or quaternary alkyl α-substituents using this method. The Strecker synthesis—the reaction of an imine or imine equivalent with hydrogen cyanide, followed by nitrile hydrolysis—is an especially versatile chemical method for the synthesis of racemic α-amino acids10,11. Asymmetric Strecker syntheses using stoichiometric amounts of a chiral reagent have been applied successfully on gram-to-kilogram scales, yielding enantiomerically enriched α-amino acids12,13,14. In principle, Strecker syntheses employing sub-stoichiometric quantities of a chiral reagent could provide a practical alternative to these approaches, but the reported catalytic asymmetric methods have seen limited use on preparative scales (more than a gram)15,16. The limited utility of existing catalytic methods may be due to several important factors, including the relatively complex and precious nature of the catalysts and the requisite use of hazardous cyanide sources. Here we report a new catalytic asymmetric method for the syntheses of highly enantiomerically enriched non-natural amino acids using a simple chiral amido-thiourea catalyst to control the key hydrocyanation step. This catalyst is robust, without sensitive functional groups, so it is compatible with aqueous cyanide salts, which are safer and easier to handle than other cyanide sources; this makes the method adaptable to large-scale synthesis. We have used this new method to obtain enantiopure amino acids that are not readily prepared by enzymatic methods or by chemical hydrogenation.

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Figure 1: Strecker synthesis of α-amino acids.
Figure 2: First-generation thiourea-catalysed asymmetric Strecker synthesis of tert -leucine.
Figure 3: Potassium cyanide-mediated Strecker synthesis.
Figure 4
Figure 5: Proposed catalytic mechanism.

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References

  1. Bhat, S. V., Nagasampagi, B. A. & Sivakumar, M. Chemistry of Natural Products 317–393 (Springer, 2005)

    Google Scholar 

  2. Wang, L. & Shultz, P. G. Expanding the genetic code. Angew. Chem. Int. Edn Engl. 44, 34–66 (2005)

    Article  CAS  Google Scholar 

  3. Tsantrizos, Y. S. Peptidomimetic therapeutic agents targeting the protease enzyme of the human immunodeficiency virus and hepatitis C virus. Acc. Chem. Res. 41, 1252–1263 (2008)

    Article  CAS  Google Scholar 

  4. Davie, E. A. C., Mennen, S. M., Xu, Y. J. & Miller, S. J. Asymmetric catalysis mediated by synthetic peptides. Chem. Rev. 107, 5759–5812 (2007)

    Article  Google Scholar 

  5. Helmchen, G. & Pfaltz, A. Phosphinooxazolines—a new class of versatile, modular P,N-ligands for asymmetric catalysis. Acc. Chem. Res. 33, 336–345 (2000)

    Article  CAS  Google Scholar 

  6. Bommarius, A. S., Schwarm, M. & Drauz, K. Comparison of different chemoenzymatic process routes to enantiomerically pure amino acids. Chimia 55, 50–59 (2001)

    CAS  Google Scholar 

  7. Breuer, M. et al. Industrial methods for the production of optically active intermediates. Angew. Chem. Int. Edn Engl. 43, 788–824 (2004)

    Article  CAS  Google Scholar 

  8. Knowles, W. S. Asymmetric hydrogenation. Acc. Chem. Res. 16, 106–112 (1983)

    Article  CAS  Google Scholar 

  9. Nájera, C. & Sansano, J. M. Catalytic asymmetric synthesis of α-amino acids. Chem. Rev. 107, 4584–4671 (2007)

    Article  Google Scholar 

  10. Block, R. J. The isolation and synthesis of the naturally occurring α-amino acids. Chem. Rev. 38, 501–571 (1946)

    Article  CAS  Google Scholar 

  11. Miller, S. L. Production of some organic compounds under possible primitive earth conditions. J. Am. Chem. Soc. 77, 2351–2361 (1955)

    Article  CAS  Google Scholar 

  12. Harada, K. Asymmetric synthesis of α-amino acids by the Strecker synthesis. Nature 200, 1201 (1963)

    Article  ADS  CAS  Google Scholar 

  13. Kuethe, J. T., Gauthier, D. R., Beutner, G. L. & Yasuda, N. A concise synthesis of (S)-N-ethoxycarbonyl-α-methylvaline. J. Org. Chem. 72, 7469–7472 (2007)

    Article  CAS  Google Scholar 

  14. Shu, L. & Wang, P. Synthesis of enantiopure Fmoc-α-methylvaline. . Org. Process Res. Dev. 12, 298–300 (2008)

    Article  CAS  Google Scholar 

  15. Gröger, H. Catalytic enantioselective Strecker reactions and analogous syntheses. Chem. Rev. 103, 2795–2827 (2003)

    Article  Google Scholar 

  16. Merino, P., Marqués-López, E., Tejero, T. & Herrara, R. P. Organocatalyzed Strecker reactions. Tetrahedron 65, 1219–1234 (2009)

    Article  CAS  Google Scholar 

  17. Sigman, M. S., Vachal, P. & Jacobsen, E. N. A general catalyst for the asymmetric Strecker reaction. Angew. Chem. Int. Edn Engl. 39, 1279–1281 (2000)

    Article  CAS  Google Scholar 

  18. Doyle, A. G. & Jacobsen, E. N. Small-molecule H-bond donors in asymmetric catalysis. Chem. Rev. 107, 5713–5743 (2007)

    Article  CAS  Google Scholar 

  19. Wenzel, A. G., Lalonde, M. P. & Jacobsen, E. N. Divergent stereoinduction mechanisms in urea-catalyzed additions to imines. Synlett 1919–1922 (2003)

  20. Reisman, S. E., Doyle, A. G. & Jacobsen, E. N. Enantioselective thiourea-catalyzed additions to oxocarbenium ions. J. Am. Chem. Soc. 130, 7198–7199 (2008)

    Article  CAS  Google Scholar 

  21. Mai, K. & Patil, G. Alkylsilyl cyanides as silylating agents. J. Org. Chem. 51, 3545–3548 (1986)

    Article  CAS  Google Scholar 

  22. Bélanger, E., Pouliot, M.-F. & Paquin, J.-F. Use of 5,5-(dimethyl)-i-Pr-PHOX as a practical equivalent to t-Bu-PHOX in asymmetric catalysis. Org. Lett. 11, 2201–2204 (2009)

    Article  Google Scholar 

  23. Ooi, T., Uematsu, Y. & Maruoka, K. Asymmetric Strecker reaction of aldimines using aqueous potassium cyanide by phase-transfer catalysis of chiral quaternary ammonium salts with a tetranaphthyl backbone. J. Am. Chem. Soc. 128, 2548–2549 (2006)

    Article  CAS  Google Scholar 

  24. Anderson, J. C., Denton, R. M., Hickin, H. G. & Wilson, C. Synthesis of dibenzofuran-1,4-diones using the Dotz benzannulation. Tetrahedron 60, 2327–2335 (2004)

    Article  CAS  Google Scholar 

  25. Corey, E. J. & Grogan, M. J. Enantioselective synthesis of alpha-amino nitriles from N-benzhydryl imines and HCN with a chiral bicyclic guanidine as catalyst. Org. Lett. 1, 157–160 (1999)

    Article  CAS  Google Scholar 

  26. Krueger, C. A. et al. Ti-catalyzed enantioselective addition of cyanide to imines. a practical synthesis of optically pure alpha-amino acids. J. Am. Chem. Soc. 121, 4284–4285 (1999)

    Article  CAS  Google Scholar 

  27. Arasappan, A. et al. Practical and efficient method for amino acid derivatives containing beta quaternary center: application toward synthesis of hepatitis C virus NS3 serine protease inhibitors. Tetrahedr. Lett. 48, 6343–6347 (2007)

    Article  CAS  Google Scholar 

  28. Mita, T. & Jacobsen, E. N. Bifunctional asymmetric catalysis with hydrogen chloride: enantioselective ring-opening of aziridines catalyzed by a phosphinothiourea. Synlett 1680–1684 (2009)

  29. Frisch, M. J. et al. Gaussian 03 Revision E.01 (Gaussian, Inc., 2004)

    Google Scholar 

  30. Zuend, S. J. & Jacobsen, E. N. Mechanism of amido-thiourea catalyzed enantioselective imine hydrocyanation: transition state stabilization via multiple non-covalent interactions. J. Am. Chem. Soc. 10.1021/ja9058958 (in the press)

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Acknowledgements

This work was supported by the NIH, and through fellowships from the American Chemical Society and Roche (to S.J.Z.) and the Natural Sciences and Engineering Research Council of Canada (to M.P.L.).

Author Contributions S.J.Z. and M.P.L. synthesized and evaluated the catalysts; M.P.C. evaluated the scope of the TMSCN-mediated reaction; S.J.Z. developed the KCN-mediated syntheses and the large-scale procedures; S.J.Z. and E.N.J. wrote the manuscript; E.N.J. guided the research.

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Authors and Affiliations

  1. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA,

    Stephan J. Zuend, Matthew P. Coughlin, Mathieu P. Lalonde & Eric N. Jacobsen

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  1. Stephan J. Zuend
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  2. Matthew P. Coughlin
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  3. Mathieu P. Lalonde
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  4. Eric N. Jacobsen
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Correspondence to Eric N. Jacobsen.

Supplementary information

Supplementary Information

This file contains Supplementary Methods, Supplementary Figures 1-8, and Supplementary Table 1. This file includes experimental details and spectroscopic characterization data, chiral HPLC traces of racemic and non-racemic ?-aminonitriles and benzyl esters of α-amino acids, 1H and 13C NMR spectra of catalyst 4e and α-amino acids, and the geometry of the calculated intermediate. (PDF 1797 kb)

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Zuend, S., Coughlin, M., Lalonde, M. et al. Scaleable catalytic asymmetric Strecker syntheses of unnatural α-amino acids. Nature 461, 968–970 (2009). https://doi.org/10.1038/nature08484

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