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Acta Chimica Sinica >

2012 , Vol. 70 >Issue 13: 1471 - 1476

DOI: https://doi.org/10.6023/A12040166

Article

Synthesis of Cyclic Tetrapeptides via Ligation of Peptide Hydrazides

  • Tang Shan ,
  • Zheng Jishen ,
  • Yang Ke ,
  • Liu Lei
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  • Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084

Received date: 2012-04-28

  Online published: 2012-05-24

Supported by

Project supported by the National Natural Science Foundation of China (Nos. 20932006 and 91013007).

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Abstract

Naturally occurring or man-made cyclic tetrapeptides have unique rigid skeletons and therefore, represent an interesting class of candidate bioactive molecules in drug discovery. However, efficient chemical synthesis of cyclic tetrapeptides often presents a difficult problem due to the large strain involved in this category of target compounds. To overcome this problem we describe in the present study the use of peptide hydrazides for the preparation of highly strained 12-membered all-L cyclic tetrapeptides. The new synthetic route starts with the easy Fmoc solid phase synthesis of a linear N-Cys-tetrapeptide hydrazide precursor. Upon quick activation by NaNO2at pH 3 and -10 ℃ for 20 min followed by treatment with a pH 7 buffer containing an external thiol (4-mercaptophenylacetic acid, 40 equiv.) at room temperature, the N-Cys-tetrapeptide hydrazide precursor is converted in situ to an N-Cys-tetrapeptide thioester. This thioester undergoes a fast intramolecular thioester exchange reaction to generate a 13-membered thiolactone intermediate. Then an S-to-N acyl shift is expected to take place to create an amide bond, which affords the desired cyclic tetrapeptide in a modest overall yield (ca. 40%). Finally, desulfurization of the cyclic peptide product can be carried out to produce the target cyclic tetrapeptide that does not contain any Cys residue. Through detailed 1H, 13C, and TOSCY NMR and HPLC analyses, it is found that the new method for tetrapeptide synthesis can be carried out at relatively high substrate concentrations (0.8-1.0 mmol/L) without causing the formation of much cyclic octapeptide byproduct. Our test also showed that the reaction can generate the desired cyclic tetrapeptide in an epimerization free manner. By using the new method we have successfully prepared several cyclic tetrapeptides including cyclo(Ala-Leu-Ala-Leu), cyclo(Ala-His-Gly-Trp), and cyclo(Ala-Val-Gly-Ile) in 18%-25% overall yields. We expect that our method of cyclic tetrapeptide synthesis may find applications in the development of cyclic peptide libraries for bioactivity screening.

Key words： cyclotetrapeptides; peptide hydrazides; ligation; acyl shift

Cite this article

Tang Shan , Zheng Jishen , Yang Ke , Liu Lei . Synthesis of Cyclic Tetrapeptides via Ligation of Peptide Hydrazides[J]. Acta Chimica Sinica, 2012 , 70(13) : 1471 -1476 . DOI: 10.6023/A12040166

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