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Stereocontrolled 1,3-nitrogen migration to access chiral α-amino acids

Abstract

α-Amino acids are essential for life as building blocks of proteins and components of diverse natural molecules. In both industry and academia, the incorporation of unnatural amino acids is often desirable for modulating chemical, physical and pharmaceutical properties. Here we report a protocol for the economical and practical synthesis of optically active α-amino acids based on an unprecedented stereocontrolled 1,3-nitrogen shift. Our method employs abundant and easily accessible carboxylic acids as starting materials, which are first connected to a nitrogenation reagent, followed by a highly regio- and enantioselective ruthenium- or iron-catalysed C(sp3)–H amination. This straightforward method displays a very broad scope, providing rapid access to optically active α-amino acids with aryl, allyl, propargyl and alkyl side chains, and also permits stereocontrolled late-stage amination of carboxylic-acid-containing drugs and natural products.

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Fig. 1: Stereocontrolled nitrene C(sp3)–H insertions for the synthesis of α-amino acids.
Fig. 2: Investigation of the reaction mechanism.
Fig. 3: Summary of proposed simplified mechanism.

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Data availability

All relevant data supporting the findings of this study, including experimental procedures and compound characterization, NMR and HPLC are available within the article and its Supplementary Information.

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Acknowledgements

This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement number 883212). Funding was also provided by the Deutsche Forschungsgemeinschaft (Me 1805/15-1). S.C. thanks Oberlin College for financial support. DFT calculations were performed using the SCIURus, the Oberlin College HPC cluster (NSF MRI 1427949), and the startup allocations awarded by Extreme Science and Engineering Discovery Environment (XSEDE TG-CHE200100).

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Authors

Contributions

E.M. and S.C. wrote the manuscript. E.M. and C.-X.Y. conceived the project and devised the experiments for the ruthenium catalysis. E.M. and X.S. devised the experiments for the iron catalysis. C.-X.Y. carried out the initial experiments and developed the ruthenium catalysis. X.S. developed the iron catalysis. S.C. performed the DFT calculations.

Corresponding authors

Correspondence to Shuming Chen or Eric Meggers.

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Competing interests

E.M., C.-X.Y. and X.S. are named inventors on a European patent application (EP22163544.4) filed by the University of Marburg on the synthesis of α-amino acids via 1,3-nitrogen migration. S.C. declares no competing interests.

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Supplementary Tables 1 and 2, Figs. 1 and 2, experimental procedures and characterization data, mechanistic studies, computational data and NMR spectra.

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Ye, CX., Shen, X., Chen, S. et al. Stereocontrolled 1,3-nitrogen migration to access chiral α-amino acids. Nat. Chem. 14, 566–573 (2022). https://doi.org/10.1038/s41557-022-00895-3

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