Scaleable catalytic asymmetric Strecker syntheses of unnatural α-amino acids

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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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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Correspondence to Eric N. Jacobsen.

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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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