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The First Total Synthesis of the Peptaibol Hypomurocin A1 and Its Conformation Analysis: an Application of the 'Azirine/Oxazolone Method'


Pradeille, Nicolas; Zerbe, Oliver; Möhle, Kerstin; Linden, Anthony; Heimgartner, Heinz (2005). The First Total Synthesis of the Peptaibol Hypomurocin A1 and Its Conformation Analysis: an Application of the 'Azirine/Oxazolone Method'. Chemistry & Biodiversity, 2:1127-1152.

Abstract

The first total synthesis of Hypomurocin A1 (HM A1) in solution phase is described. As members of the peptaibol family, hypomurocins are constituted by two groups of peptides: six undecapeptides (undecamers) in the HM A group and six octadecapeptides (18-mers) in the HM B group. The synthesis presented has been successfully achieved by the 'azirine/oxazolone method' to introduce the two Aib-Pro sequences included in this undecapeptaibol in one step with methyl 2,2-dimethyl-2H-azirine-3-prolinate as the building block. The coupling reactions of the Z-protected amino acids or peptide acids involved the use of N,N,N ,N -tetramethyluronium tetrafluoroborate (TBTU) and 1-hydroxybenzotriazole (HOBt), and led to the peptides in good-to-very-good yields. The peptides were purified by reverse-phase HPLC and characterized by NMR spectroscopy (1H, 13C, COSY, TOCSY, HSQC, HMBC, ROESY), ESI-MS, IR, elemental analysis, optical rotation, and X-ray crystallography. An NMR analysis of HM A1 was also carried out in deuterated micelles to perform a structural comparison of the helix in solution and in membranes.

Abstract

The first total synthesis of Hypomurocin A1 (HM A1) in solution phase is described. As members of the peptaibol family, hypomurocins are constituted by two groups of peptides: six undecapeptides (undecamers) in the HM A group and six octadecapeptides (18-mers) in the HM B group. The synthesis presented has been successfully achieved by the 'azirine/oxazolone method' to introduce the two Aib-Pro sequences included in this undecapeptaibol in one step with methyl 2,2-dimethyl-2H-azirine-3-prolinate as the building block. The coupling reactions of the Z-protected amino acids or peptide acids involved the use of N,N,N ,N -tetramethyluronium tetrafluoroborate (TBTU) and 1-hydroxybenzotriazole (HOBt), and led to the peptides in good-to-very-good yields. The peptides were purified by reverse-phase HPLC and characterized by NMR spectroscopy (1H, 13C, COSY, TOCSY, HSQC, HMBC, ROESY), ESI-MS, IR, elemental analysis, optical rotation, and X-ray crystallography. An NMR analysis of HM A1 was also carried out in deuterated micelles to perform a structural comparison of the helix in solution and in membranes.

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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
Scopus Subject Areas:Physical Sciences > Bioengineering
Life Sciences > Biochemistry
Physical Sciences > General Chemistry
Life Sciences > Molecular Medicine
Life Sciences > Molecular Biology
Uncontrolled Keywords:Molecular Medicine, Biochemistry, Bioengineering, General Chemistry, Molecular Biology, General Medicine
Language:English
Date:2005
Deposited On:07 Dec 2012 15:50
Last Modified:30 Jul 2020 06:18
Publisher:Wiley-VCH Verlag Berlin
ISSN:1612-1872
Funders:Swiss National Science Foundation, F. Hoffmann-La Roche AG, Basel
OA Status:Closed
Publisher DOI:https://doi.org/10.1002/cbdv.200590084
Project Information:
  • : FunderSNSF
  • : Grant ID
  • : Project TitleSwiss National Science Foundation
  • : Funder
  • : Grant ID
  • : Project TitleF. Hoffmann-La Roche AG, Basel

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