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A new protecting group for tryptophan in solid-phase peptide synthesis which protectsagainst acid-catalyzed side reactions and facilitates purification by HPLC
Stockholm University, Faculty of Science, Department of Neurochemistry.
Stockholm University, Faculty of Science, Department of Neurochemistry.ORCID iD: 0000-0003-1003-6472
2009 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 50, no 24, 2976-2978 p.Article in journal (Refereed) Published
Abstract [en]

The indole nucleus of Z-Trp-OBzl is modified by acylation of the indole nitrogen using Boc-N-methyl butyric acid followed by catalytic hydrogenation and introduction of the Fmoc group. The resulting derivative, Fmoc-Trp(Boc-Nmbu)-OH, is incorporated into peptide chains via solid-phase peptide synthesis (SPPS). After assembly of the peptide chain, the Boc group is cleaved by treatment with TFA. The peptide is isolated with the tryptophan residue modified with a cationic 4-(N-methylamino) butanoyl group, which improves the solubility of the peptide during HPLC purification. On treatment of the purified peptide at pH 9.5, the Nmbu group undergoes an intramolecular cyclization reaction; this results in the fully deprotected peptide and N-methylpyrrolidone.

Place, publisher, year, edition, pages
2009. Vol. 50, no 24, 2976-2978 p.
National Category
Chemical Sciences
URN: urn:nbn:se:su:diva-27554DOI: 10.1016/j.tetlet.2009.04.014ISI: 000266188300036OAI: diva2:214747
Available from: 2009-05-06 Created: 2009-05-06 Last updated: 2015-03-16Bibliographically approved
In thesis
1. Development and characterisation of protecting groups that enhance the solubility of synthetic peptides: Methods to improve the aqueous solubility of hydrophobic peptides
Open this publication in new window or tab >>Development and characterisation of protecting groups that enhance the solubility of synthetic peptides: Methods to improve the aqueous solubility of hydrophobic peptides
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Chemical synthesis of peptides is generally performed by solid phase peptide synthesis (SPPS). Although SPPS is a rapid and convenient method to prepare peptides, the major methodological problem in SPPS is related to solvation/solubility. Poor solvation of the peptide during the synthesis on solid phase will frequently lead to deletion peptides and if the peptide is poorly soluble after it has been cleaved from the resin, it can be difficult to purify by liquid chromatography. In order to increase the solubility of peptides, two new amino acid derivatives and a modification of the 2-hydroxy-4-methoxy-benzyl (Hmb) group, a protecting group for the peptide bond, have been developed. The Boc-N-methyl-N-[(2-methylamino)ethyl]carbamoyl (Boc-Nmec) group was used for protection of aromatic hydroxyl groups of tyrosine and the Hmb group. The Boc-4-(N-methyl-amino)butanoyl (Boc-Nmbu) group was used for protection of the indole nitrogen on tryptophan. The new derivatives were introduced into model peptides by standard protocol for Fmoc chemistry. The Boc protection of the Nmec/Nmbu group is removed during the cleavage of the peptide from the resin but the Nmec/Nmbu group is still attached to the peptide. The Nmec/Nmbu group contains a secondary amino group that is protonated at low pH and thereby increases the solubility during purification and handling of the peptide in aqueous solutions. By raising the pH the Nmec (pH 8)/Nmbu (pH 9) group is cleaved by an intramolecular cyclization reaction to give the fully deprotected peptide. Amyloid b (1-42) is a large peptide that is very difficult both to assemble on solid phase and to purify by HPLC.  It is shown that by using the Boc-Nmec protected dipeptides, amyloid b (1-42) could be synthesized by SPPS with only traces of by-products and that the peptide was easy to purify by HPLC. It is likely that the new protecting groups would be very useful in synthesis and handling of hydrophobic peptides.



Place, publisher, year, edition, pages
Stockholm: Department of Neurochemistry, Stockholm University, 2009. 69 p.
Solid phase peptide synthesis, Fmoc chemistry, solubility problems, tryptophan, tyrosine, Nmec, Nmbu
National Category
Organic Chemistry
Research subject
Neurochemistry and Molecular Neurobiology
urn:nbn:se:su:diva-27202 (URN)978-91-7155-867-1 (ISBN)
Public defence
2009-05-29, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 13:00 (English)
Available from: 2009-05-08 Created: 2009-04-24 Last updated: 2015-03-16Bibliographically approved

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Undén, Anders
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