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Synthesis and conformational analysis of 18-membered Aib-containing cyclohexapeptides


Jeremic, Tatjana; Linden, Anthony; Möhle, Kerstin; Heimgartner, Heinz (2005). Synthesis and conformational analysis of 18-membered Aib-containing cyclohexapeptides. Tetrahedron, 61(7):1871-1883.

Abstract

The synthesis and conformational analysis of two Aib-containing cyclic hexapeptides, cyclo(Gly-Aib-Leu-Aib-Phe-Aib) 1 and cyclo(Leu-Aib-Phe-Gly-Aib-Aib) 2, is described. The linear precursors of 1 and 2 were prepared using solution phase techniques, and the cyclization efficiency of three different coupling reagents (HATU, PyAOP, DEPC) was examined. The success of the cyclization was found to be reagent dependent. Solid-state conformational analysis of 1 and 2 was performed by X-ray crystallography and has revealed some unusual features as all three Aib residues of 1 assume nonhelical conformations. Furthermore, the residue Aib4 adopts an extended conformation (fZK175.9(3)8, jZC178.6(2)8), which is, to the best of our knowledge, the first observation of an Aib residue adopting an extended conformation in a cyclopeptide. The structure of 1 is also a rare example in which an Aib residue occupies the (iC1) position of a type II0 b-turn, stabilized by a bifurcated hydrogen bond. The cyclic peptide 2 adopts a more regular conformation in the solid state, consisting of two fused b-turns of type I/I0, stabilized by a pair of intramolecular hydrogen bonds. In addition, the conformational study of the cyclic peptide 1 in DMSO-d6 by NMR spectroscopy and molecular dynamics simulations revealed a structure, which is very similar to its structure in the crystalline state.

Abstract

The synthesis and conformational analysis of two Aib-containing cyclic hexapeptides, cyclo(Gly-Aib-Leu-Aib-Phe-Aib) 1 and cyclo(Leu-Aib-Phe-Gly-Aib-Aib) 2, is described. The linear precursors of 1 and 2 were prepared using solution phase techniques, and the cyclization efficiency of three different coupling reagents (HATU, PyAOP, DEPC) was examined. The success of the cyclization was found to be reagent dependent. Solid-state conformational analysis of 1 and 2 was performed by X-ray crystallography and has revealed some unusual features as all three Aib residues of 1 assume nonhelical conformations. Furthermore, the residue Aib4 adopts an extended conformation (fZK175.9(3)8, jZC178.6(2)8), which is, to the best of our knowledge, the first observation of an Aib residue adopting an extended conformation in a cyclopeptide. The structure of 1 is also a rare example in which an Aib residue occupies the (iC1) position of a type II0 b-turn, stabilized by a bifurcated hydrogen bond. The cyclic peptide 2 adopts a more regular conformation in the solid state, consisting of two fused b-turns of type I/I0, stabilized by a pair of intramolecular hydrogen bonds. In addition, the conformational study of the cyclic peptide 1 in DMSO-d6 by NMR spectroscopy and molecular dynamics simulations revealed a structure, which is very similar to its structure in the crystalline state.

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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:2005
Deposited On:26 Nov 2012 16:35
Last Modified:05 Apr 2016 16:06
Publisher:Elsevier
Series Name:Tetrahedron
ISSN:0040-4020
Funders:Swiss National Science Foundation, F. Hoffmann-La Roche AG, Basel
Publisher DOI:https://doi.org/10.1016/j.tet.2004.12.012

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