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α-Amino acid and peptide synthesis using catalytic cross-dehydrogenative coupling

Nature Synthesis volume 1, pages 304–312 (2022)Cite this article

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Abstract

Ionic or radical α-amino Schiff base methods are well known for the synthesis of α,α-disubstituted α-amino acids. However, the incorporation of sterically demanding groups is challenging with ionic methods, and radical methods require prefunctionalization of the substrates. Now we have developed a dehydrogenative coupling process of α-amino acid Schiff bases with hydrocarbon feedstocks for the synthesis of α,α-disubstituted α-amino acid derivatives. These α-amino acid derivatives were transformed into C- and N-protected amino acids, which could be easily incorporated into peptide synthesis. A range of α-amino acid derivatives could be readily accessed, which includes, notably, those that bear contiguous quaternary centres. Circular dichroism measurements show that the helical peptide structure is stabilized by the highly sterically congested unnatural α-amino acid. Mechanistic studies revealed that deprotonation of the α-amino acid Schiff base is a turnover-limiting step and the use of an enhanced Brønsted basic copper(I) tert-butoxide complex produced a superior catalytic performance. Photoinduction of the catalytic reaction, using blue light-emitting diode radiation, allowed the reaction to proceed without external heating.

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Fig. 1: Amino acid Schiff base for α,α-disubstituted amino acid synthesis and optimization study.
Fig. 2: Peptide modification enabled highly congested dipeptides and transformation of the product.
Fig. 3: Peptide synthesis and conformational analysis.
Fig. 4: Series of mechanistic studies and proposed catalytic cycle.
Fig. 5: Improved catalytic conditions driven by a mechanistic study.

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Data availability

The data supporting the findings of this study are available within the article and its Supplementary Information.

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Acknowledgements

This work was financially supported by JSPS KAKENHI grant no. JP15H05846 in Middle Molecular Strategy and no. JP18H04263 in Precisely Designed Catalysts with Customized Scaffolding, a Grant-in-Aid for Scientific Research (B) (no. 17H03972 and no. 21H02607), a Grant-in-Aid for Challenging Research (Exploratory) (no. 19K22501), Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS) (no. JP20am0101091) and no. JP21ak0101167 from AMED. T. Tsuji, and T. Tanaka thank the JSPS for predoctoral fellowships. R.Y. thanks the Qdai-jump Research Program, the Takeda Science Foundation, the Uehara Memorial Foundation, the Noguchi Institute and the Astellas Foundation for Research on Metabolic Disorders for financial support. We are grateful to T. Koike at the Tokyo Institute of Technology for fruitful discussions about photoredox chemistry, to A. Ojida, E. Kawanishi and S. Uchinomiya at Kyushu University for fruitful discussions about solid-phase peptide synthesis and to Y. Matsuoka at Kyushu University for electrochemical analysis.

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  1. These authors contributed equally: Taro Tsuji, Kayoko Hashiguchi.

Authors and Affiliations

  1. Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Japan

    Taro Tsuji, Kayoko Hashiguchi, Mana Yoshida, Tetsu Ikeda, Yunosuke Koga, Yusaku Honda, Tsukushi Tanaka, Daisuke Takahashi, Ryo Yazaki & Takashi Ohshima

  2. Artificial Intelligence Center for Health and Biomedical Research, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan

    Suyong Re & Kenji Mizuguchi

  3. Institute for Protein Research, Osaka University, Osaka, Japan

    Kenji Mizuguchi

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  1. Taro Tsuji
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Contributions

T. Tsuji, R.Y. and T.O. conceived the work. T. Tsuji, K.H., M.Y., T.I., Y.K., Y.H., T. Tanaka and R.Y. designed and carried out the experiments. S.R. and K.M. performed the in silico analysis. D.T. performed the conformational analysis of peptides. All the authors analysed the data, discussed the results and co-wrote the manuscript.

Corresponding authors

Correspondence to Ryo Yazaki or Takashi Ohshima.

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A provisional patent application for part of this work has been filed (Kyushu University, PCT/JP2019/041918).

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Nature Synthesis thanks Chao-Jun Li, Patrick Walsh and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Thomas West was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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44160_2022_37_MOESM1_ESM.pdf

Supplementary Information Supplementary Figs. 5-1, 8-1–8-6 and 9-1–9-3, Discussion (In silico Analysis) and Tables 10-1 and 10-2.

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Tsuji, T., Hashiguchi, K., Yoshida, M. et al. α-Amino acid and peptide synthesis using catalytic cross-dehydrogenative coupling. Nat. Synth 1, 304–312 (2022). https://doi.org/10.1038/s44160-022-00037-0

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