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Asymmetric α-arylation of amino acids

Abstract

Quaternary amino acids, in which the α-carbon that bears the amino and carboxyl groups also carries two carbon substituents, have an important role as modifiers of peptide conformation and bioactivity and as precursors of medicinally important compounds1,2. In contrast to enantioselective alkylation at this α-carbon, for which there are several methods3,4,5,6,7,8, general enantioselective introduction of an aryl substituent at the α-carbon is synthetically challenging9. Nonetheless, the resultant α-aryl amino acids and their derivatives are valuable precursors to bioactive molecules10,11. Here we describe the synthesis of quaternary α-aryl amino acids from enantiopure amino acid precursors by α-arylation without loss of stereochemical integrity. Our approach relies on the temporary formation of a second stereogenic centre in an N′-arylurea adduct12 of an imidazolidinone derivative6 of the precursor amino acid, and uses readily available enantiopure amino acids both as a precursor and as a source of asymmetry. It avoids the use of valuable transition metals, and enables arylation with electron-rich, electron-poor and heterocyclic substituents. Either enantiomer of the product can be formed from a single amino acid precursor. The method is practical and scalable, and provides the opportunity to produce α-arylated quaternary amino acids in multi-gram quantities.

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Fig. 1: Stereoselective arylation of amino acids.
Fig. 2: Arylation of amino acids by way of imidazolidinone ureas.
Fig. 3: Scope of the imidazolidinone arylation: amino acids and migrating groups.
Fig. 4: Mechanism of the rearrangement.

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Acknowledgements

We acknowledge funding from the EPSRC (GR/L018527) and ERC (Advanced Grant ROCOCO and Proof of Concept grant QUATERMAIN), and we are grateful to M. M. Amer for assistance with the synthesis of starting materials.

Reviewer information

Nature thanks T. Kawabata and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Authors

Contributions

D.J.L., J.W.W. and J.C. devised the experiments; D.J.L. and J.W.W. carried out the experiments; D.J.L., J.W.W. and J.C. analysed the results and wrote the paper.

Corresponding author

Correspondence to Jonathan Clayden.

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The authors have filed a patent on this work (GB1621512.1).

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Extended data figures and tables

Extended Data Table 1 Optimizing the synthesis of 3
Extended Data Table 2 Optimizing the rearrangement of 3 to 4

Supplementary information

Supplementary Information

This file contains: General Information, General Procedures, Experimental Procedures and Characterisation Data, 1H and 13C NMR Spectra, HPLC and SFC Traces, X-Ray Crystallographic Data, Crossover Experiment, In situ IR (ReactIR), and References

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Cite this article

Leonard, D.J., Ward, J.W. & Clayden, J. Asymmetric α-arylation of amino acids. Nature 562, 105–109 (2018). https://doi.org/10.1038/s41586-018-0553-9

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Keywords

  • Quaternary Amino Acid
  • Imidazolidinone
  • Enantiopure Amino Acids
  • Minor Diastereoisomer
  • Tert-butyl Isocyanate

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