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Synthesis of non-canonical amino acids through dehydrogenative tailoring

Nature volume 634, pages 352–358 (2024)Cite this article

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Abstract

Amino acids are essential building blocks in biology and chemistry. Whereas nature relies on a small number of amino acid structures, chemists desire access to a vast range of structurally diverse analogues1,2,3. The selective modification of amino acid side-chain residues represents an efficient strategy to access non-canonical derivatives of value in chemistry and biology. While semisynthetic methods leveraging the functional groups found in polar and aromatic amino acids have been extensively explored, highly selective and general approaches to transform unactivated C–H bonds in aliphatic amino acids remain less developed4,5. Here we disclose a stepwise dehydrogenative method to convert aliphatic amino acids into structurally diverse analogues. The key to the success of this approach lies in the development of a selective catalytic acceptorless dehydrogenation method driven by photochemical irradiation, which provides access to terminal alkene intermediates for downstream functionalization. Overall, this strategy enables the rapid synthesis of new amino acid building blocks and suggests possibilities for the late-stage modification of more complex oligopeptides.

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Fig. 1: Strategies to access non-canonical amino acids.
Fig. 2: Development of the dehydrogenation method.
Fig. 3: Product derivatization and elaboration.
Fig. 4: Dehydrogenation of oligopeptide substrates.
Fig. 5: Peptide modification enabled by dehydrogenative tailoring.

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Data availability

All data supporting the findings of this paper are available in the main text or the Supplementary Information.

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Acknowledgements

We thank J. Yang (MIT) for HPLC separation of product 2p and S. Garhwal (MIT) for supercritical fluid chromatography data collection. Financial support for this work was provided by the National Institutes of Health (GM146248) and the National Science Foundation (NSF) through a Graduate Research Fellowship to G.O. (DGE1745303).

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  1. These authors contributed equally: Xin Gu, Yu-An Zhang

Authors and Affiliations

  1. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA

    Xin Gu, Yu-An Zhang, Shuo Zhang, Leon Wang, Xiyun Ye, Gino Occhialini, Jonah Barbour, Bradley L. Pentelute & Alison E. Wendlandt

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Contributions

A.E.W., X.G. and Y.-A.Z. conceived the work, designed experiments and analysed the data. L.W. and S.Z. contributed equally to substrate synthesis and characterization. X.Y. and B.L.P. provided expertise on the synthesis and analysis of oligopeptides. G.O. and J.B. performed exploratory experiments establishing the feasibility of terminal-selective aliphatic dehydrogenation. A.E.W., X.G. and Y.-A.Z. drafted the manuscript with input from all authors. A.E.W. directed the research. All authors have given approval to the final version of the manuscript.

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Correspondence to Alison E. Wendlandt.

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Gu, X., Zhang, YA., Zhang, S. et al. Synthesis of non-canonical amino acids through dehydrogenative tailoring. Nature 634, 352–358 (2024). https://doi.org/10.1038/s41586-024-07988-8

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