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Total synthesis of the peptaibols hypomurocin A3 and hypomurocin A5, and their conformation analysis


Pradeille, Nicolas; Tzouros, Manuel; Möhle, Kerstin; Linden, Anthony; Heimgartner, Heinz (2012). Total synthesis of the peptaibols hypomurocin A3 and hypomurocin A5, and their conformation analysis. Chemistry & Biodiversity, 9(11):2528-2558.

Abstract

The total syntheses of hypomurocin A3 and hypomuricin A5 (HMA3 and HMA5, resp.) in solution phase are described. These syntheses have been successfully achieved by applying the azirine/oxazolone method to introduce the two Aib-Pro units into the backbone of these undecapeptaibols in one step with methyl 2,2-dimethyl-2H-azirine-3-prolinate as the Aib-Pro synthon. The coupling of Z-protected (Z = (benzyloxy)carbonyl) amino acids or peptide acids with amino acid tert-butyl esters and of peptide
segments was carried out according to the TBTU (= O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate) and HOBt (= 1-hydroxybenzotriazole) protocol. Purification by reversed-phase HPLC gave the peptides in pure form. The products were characterized by optical rotation,NMR and IR spectroscopy, mass spectrometry, and elemental analysis. The crystal structures of HM A3 and of an octapeptide fragment of HM A5 could be obtained. An NMR analysis was also carried out with HM A3
and HM A5 to determine their conformations in solution. A global structural comparison between the three sequences of HM A1, HM A3, and HM A5 was performed, as well as the HPLC correlation of the natural HM A family and the synthetic samples.

Abstract

The total syntheses of hypomurocin A3 and hypomuricin A5 (HMA3 and HMA5, resp.) in solution phase are described. These syntheses have been successfully achieved by applying the azirine/oxazolone method to introduce the two Aib-Pro units into the backbone of these undecapeptaibols in one step with methyl 2,2-dimethyl-2H-azirine-3-prolinate as the Aib-Pro synthon. The coupling of Z-protected (Z = (benzyloxy)carbonyl) amino acids or peptide acids with amino acid tert-butyl esters and of peptide
segments was carried out according to the TBTU (= O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate) and HOBt (= 1-hydroxybenzotriazole) protocol. Purification by reversed-phase HPLC gave the peptides in pure form. The products were characterized by optical rotation,NMR and IR spectroscopy, mass spectrometry, and elemental analysis. The crystal structures of HM A3 and of an octapeptide fragment of HM A5 could be obtained. An NMR analysis was also carried out with HM A3
and HM A5 to determine their conformations in solution. A global structural comparison between the three sequences of HM A1, HM A3, and HM A5 was performed, as well as the HPLC correlation of the natural HM A family and the synthetic samples.

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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:November 2012
Deposited On:30 Nov 2012 14:05
Last Modified:05 Apr 2016 16:06
Publisher:Wiley-VCH Verlag Berlin
ISSN:1612-1872
Funders:Swiss National Science Foundation, F. Hoffmann-La Roche AG, Basel
Publisher DOI:https://doi.org/10.1002/cbdv.201200285
PubMed ID:23161633

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