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Synthesis of Aib-Pro Oligopeptides by repeated Azirine coupling with the Aib-Pro synthon


Stoykova, Svetlana A; Linden, Anthony; Heimgartner, Heinz (2012). Synthesis of Aib-Pro Oligopeptides by repeated Azirine coupling with the Aib-Pro synthon. Helvetica Chimica Acta, 95(8):1325-1350.

Abstract

A new synthesis of (Aib-Pro)n oligopeptides (n = 2, 3, and 4) via azirine coupling by using the dipeptide synthon methyl N-(2,2-dimethyl-2H-azirin-3-yl)-l-prolinate (1b; Fig. 1) is presented. The most important feature of the employed protocol is that no activation of the acid component is necessary, i.e., no additional reagents are required, and the coupling reaction is performed under mild conditions at room temperature. As an attempt to provide an answer to the question of the preferred conformation of the prepared molecules, we carried out experiments by using NMR techniques and X-ray crystallography. For example, in the case of the hexapeptide 11, it was possible to compare the conformations in the crystalline state and in solution. After the selective hydrolysis of the methyl ester p-BrBz-(Aib-Pro)4-OMe (13) under basic conditions, the corresponding octapeptide acid was obtained, which was then converted into the octapeptide amide p-BrBz-(Aib-Pro)4-NHC6H13 (15) by using standard coupling conditions and activating reagents (HOBt/TBTU/DIEA) of the peptide synthesis. The conformation of this compound, as well as those of the tetrapeptides 14 and 18, was also established by X-ray crystallography and in solution by NMR techniques. In the crystalline state, a beta-bend ribbon structure is the preferred conformation, and similar conformations are formed in solution.

Abstract

A new synthesis of (Aib-Pro)n oligopeptides (n = 2, 3, and 4) via azirine coupling by using the dipeptide synthon methyl N-(2,2-dimethyl-2H-azirin-3-yl)-l-prolinate (1b; Fig. 1) is presented. The most important feature of the employed protocol is that no activation of the acid component is necessary, i.e., no additional reagents are required, and the coupling reaction is performed under mild conditions at room temperature. As an attempt to provide an answer to the question of the preferred conformation of the prepared molecules, we carried out experiments by using NMR techniques and X-ray crystallography. For example, in the case of the hexapeptide 11, it was possible to compare the conformations in the crystalline state and in solution. After the selective hydrolysis of the methyl ester p-BrBz-(Aib-Pro)4-OMe (13) under basic conditions, the corresponding octapeptide acid was obtained, which was then converted into the octapeptide amide p-BrBz-(Aib-Pro)4-NHC6H13 (15) by using standard coupling conditions and activating reagents (HOBt/TBTU/DIEA) of the peptide synthesis. The conformation of this compound, as well as those of the tetrapeptides 14 and 18, was also established by X-ray crystallography and in solution by NMR techniques. In the crystalline state, a beta-bend ribbon structure is the preferred conformation, and similar conformations are formed in solution.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Language:English
Date:August 2012
Deposited On:22 Aug 2012 08:08
Last Modified:05 Apr 2016 15:56
Publisher:Verlag Helvetica Chimica Acta
ISSN:0018-019X
Funders:Swiss National Science Foundation , F. Hoffmann-La Roche AG, Basel
Publisher DOI:https://doi.org/10.1002/hlca.201200136

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