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Synthesis of peptide macrocycles using unprotected amino aldehydes

Nature Protocols volume 5, pages 1813–1822 (2010)Cite this article

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Abstract

This protocol describes a method for synthesizing peptide macrocycles from linear peptide precursors, isocyanides and aziridine aldehydes. The effects of the reaction components on the efficiency of the process are discussed. Macrocyclization is exemplified by the preparation of a nine-membered ring peptide macrocycle. The product is further functionalized by nucleophilic opening of the aziridine ring with a fluorescent thiol. This transformation constitutes a useful late-stage functionalization of a macrocyclic peptide molecule. The experimental section describes the selection of the required starting materials, and the preparation of a representative aziridine-2-carboxaldehyde dimer. The synthesis and isolation of the peptide macrocycle can be accomplished in 6 h, and the ring-opening requires approximately 6–8 h. The aziridine-2-carboxaldehyde reagent is commercially available or can be synthesized from readily available starting materials in approximately 4 d. The strategy described is not limited to the specific peptide, isocyanide, aziridine aldehyde or nucleophile used in the representative synthesis.

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Figure 1
Figure 2
Figure 3
Figure 4: Aziridine formation by the Mitsunobu reaction.
Figure 5: Synthesis of aziridine aldehyde dimer by DIBAL reduction.
Figure 6: Macrocyclization of Pro-Leu.
Figure 7
Figure 8: Labeling of a macrocycle with a fluorescent thiol.
Figure 9

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Author notes

  1. Ryan Hili

    Present address: Present address: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA.,

Authors and Affiliations

  1. Department of Chemistry, Davenport Research Laboratories, University of Toronto, Toronto, Ontario, Canada

    Benjamin H Rotstein, Vishal Rai, Ryan Hili & Andrei K Yudin

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Contributions

B.R., V.R. and R.H. carried out the syntheses and characterization. A.Y. designed the experiments and supervised the overall project. All authors co-wrote the manuscript.

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Correspondence to Andrei K Yudin.

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Rotstein, B., Rai, V., Hili, R. et al. Synthesis of peptide macrocycles using unprotected amino aldehydes. Nat Protoc 5, 1813–1822 (2010). https://doi.org/10.1038/nprot.2010.127

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