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O-to-O acyl transfer for epimerization-free peptide C-terminal salicylaldehyde ester synthesis

Nature Synthesis volume 3, pages 1049–1060 (2024)Cite this article

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Abstract

Peptide salicylaldehyde esters are the requisite coupling partner in Ser/Thr ligation reactions towards chemical protein synthesis. In general, it would be cost-effective and efficient to use side-chain-protected peptide acids, after Fmoc solid-phase peptide synthesis, for direct C-terminal derivatization; however, this has yet to be achieved, due to an intrinsic epimerization pathway. Here we report the development of 2-(dichloromethyl)phenol as a reagent that can directly form peptide salicylaldehyde esters in an epimerization-free manner. Mechanistic studies reveal that the 2-(dichloromethyl)phenol reagent serves as a source of highly reactive quinone methide species that can be trapped by the peptide C-terminal carboxylate to give α-chloroesters, followed by an Obenzylic-to-Ophenolic acyl transfer and chloride extrusion process. The peptide salicylaldehyde ester reaction products have been applied in the convergent total chemical synthesis of linker histone H1.2 using sequential Ser/Thr ligation reactions.

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Fig. 1: Overview of intramolecular acyl transfer processes and design of the DCP-facilitated salicylaldehyde ester formation.
Fig. 2: Synthesis of the DCP reagent and the condition optimization of the SAL ester formation in the model system.
Fig. 3: Evaluation of the effect of C-terminal residues on the peptide SAL ester formation using DCP reagent.
Fig. 4: Substrate scope of the peptide SAL ester formation using DCP reagent.
Fig. 5: Mechanism study of the SAL ester formation using DCP reagent.
Fig. 6: Computational study of the mechanism of DCP reagent mediated SAL ester formation.
Fig. 7: Convergent synthesis of histone H1.2 via Ser/Thr ligations.
Fig. 8: Characterizations of synthetic histone H1.2 protein.

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All data supporting the findings of this study are available in the main text and Supplementary Information. Source data are provided with this paper.

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Acknowledgements

The work was supported by the Grants Research Council of University Grants Committee of Hong Kong (C7017-18G, 17302621, 17306521 and AoE/P-706/16) and the National Natural Science Foundation of China (22177097).

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  1. These authors contributed equally: Wang Xia, Bing-Wen Li.

Authors and Affiliations

  1. Department of Chemistry, the State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Hong Kong SAR, P. R. China

    Wang Xia, Zhixiang Zhong, Jiamei Liu, Han Liu & Xuechen Li

  2. Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing, P. R. China

    Bing-Wen Li & Zhi-Xiang Yu

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Contributions

X.L. conceived and supervised the study. X.L. and W.X. designed experiments. W.X., Z.Z. and J.L. performed experiments. B.-W.L. and Z.-X.Y. performed the computational study. X.L., H.L., W.X. and B.-W.L. analysed the data. X.L. and H.L. wrote the paper.

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Supplementary Information

Supplementary Figs. 1–76, Table 1, additional experimental procedures, computational calculation details and characterization data.

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Supplementary Data 1

Cartesian coordinates of intermediates and transition states.

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Source Data Fig. 8b

Scanned SDS–PAGE of synthetic and expressed histone H1.2. The three lanes on the right side are not related to this work.

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Xia, W., Li, BW., Zhong, Z. et al. O-to-O acyl transfer for epimerization-free peptide C-terminal salicylaldehyde ester synthesis. Nat. Synth 3, 1049–1060 (2024). https://doi.org/10.1038/s44160-024-00570-0

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