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. 2009 Apr 22;131(15):5432-7.
doi: 10.1021/ja808705v.

Toward homogeneous erythropoietin: fine tuning of the C-terminal acyl donor in the chemical synthesis of the Cys29-Gly77 glycopeptide domain

Yu Yuan  1 , Jin Chen, Qian Wan, Zhongping Tan, Gong Chen, Cindy Kan, Samuel J Danishefsky
Affiliations

Toward homogeneous erythropoietin: fine tuning of the C-terminal acyl donor in the chemical synthesis of the Cys29-Gly77 glycopeptide domain

Yu Yuan et al. J Am Chem Soc. .

Abstract

Described herein is the chemical synthesis of the Cys(29)-Gly(77) glycopeptide domain (22) of erythropoietin. Our initial ligation strategy targeted a C --> N termini condensation between glycopeptide 3 and peptide 4. However, the reaction was hindered by the "unattainable" reactivity, mismatched polarity, and severe aggregation of the (glyco)peptide substrates. In contrast, by tuning the C-terminal acyl donor and using smaller peptide fragments, the Cys(29)-Gly(77) glycopeptide domain of erythropoietin was prepared through unconventional N --> C termini condensation reactions. The use of a p-cyanonitrophenyl ester and the development of a masked thiophenyl ester as acyl donors enabled us to promptly access glycopeptides bearing complex carbohydrates and offer potential synthetic applications beyond our current work.

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Figures

Scheme 1
Scheme 1
Retrosynthetic analysis of Epo and fragment Cys29-Gly77.
Scheme 2
Scheme 2
Initial construction of fragment Epo 29–77.
Scheme 3
Scheme 3
Successful fragment condensation to deliver EPO(29–77) with disaccharide.
Scheme 4
Scheme 4
Lansbury aspartylation between dodecasaccharide and reactive acyl donors
Scheme 5
Scheme 5
Revised retrosynthetic analysis for Epo 29–77
Scheme 6
Scheme 6
Potential problem associated with hydrolysis of the masked thioester.
Scheme 7
Scheme 7
Preparation of masked thiophenol 18
Scheme 8
Scheme 8
Completion of synthesis EPO(29–77)
See this image and copyright information in PMC

References

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