NMR‐Solution Structures of Fluoro‐Substituted β‐Peptides: A 314‐Helix and a Hairpin Turn. The First Case of a 90° OC?C?F Dihedral Angle in an α‐Fluoro‐Amide Group |
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Authors: | Raveendra I. Mathad Bernhard Jaun Oliver Flögel James Gardiner Markus Löweneck Jeroen D. C. Codée Peter H. Seeberger Dieter Seebach Michael K. Edmonds Florian H. M. Graichen Andrew D. Abell |
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Affiliation: | 1. Laboratorium für Organische Chemie, Departement Chemie und Angewandte Biowissenschaften, ETH‐Zürich, HCI H?nggerberg, Wolfgang‐Pauli‐Strasse 10, CH‐8093 Zürich;2. Part of the Ph.D. Thesis of R.?I.?M., ETH Dissertation No. 17209.;3. Postdoctoral Research Fellow at ETH‐Zürich, 2004–2006, financed by the Deutsche Forschungsgemeinschaft, by the Swiss National Science Foundation, Project No. 200020‐100182, and by Novartis Pharma AG, Basel.;4. Postdoctoral Research Fellow at ETH‐Zürich, 2004–2007, financed by the New Zealand Foundation for Research Science and Technology, Project No. SWSS0401.;5. Postdoctoral Research Fellow at ETH‐Zürich, financed by the Swiss National Science Foundation, Project No. 200020‐109065/1.;6. Postdoctoral Fellow in the group of Prof. P.?H. Seeberger, ETH‐Zürich 2005–2006.;7. Department of Chemistry, University of Canterbury, Private Bag 4800, Christchurch, New Zealand;8. Current address, School of Chemistry & Physics, University of Adelaide, SA 5005, Australia. |
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Abstract: | To further study the preference of the antiperiplanar (ap) conformation in α‐fluoro‐amide groups, two β‐peptides, 1 and 2 , containing a (2‐F)‐β3hAla and a (2‐F)‐β2hPhe residue, have been synthesized. Their NMR‐solution structures in CD3OH were determined and compared with those of non‐F‐substituted analogs, 3 and 4a . While we have found in a previous investigation (Helv. Chim. Acta 2005 , 88, 266) that a stereospecifically introduced F‐substituent in the central position of a β‐heptapeptide is capable of ‘breaking’ the 314‐helical structure by enforcing the F? C? C?O ap‐conformation, we could now demonstrate that the same procedure leads to a structure with the unfavorable ca. 90° F? C? C?O dihedral angle, enforced by the 314‐helical folding in a β‐tridecapeptide (cf. 1 ; Fig. 4). This is interpreted as a consequence of cooperative folding in the longer β‐peptide. A F‐substituent placed in the turn section of a β‐peptidic hairpin turn was shown to be in an ap‐arrangement with respect to the neighboring C?O bond (cf. 2 ; Fig. 7). Analysis of the non‐F‐substituted β‐tetrapeptides (with helix‐preventing configurations of the two central β2/β3‐amino acid residues) provides unusually tight hairpin structural clusters (cf. 3 and 4a ; Figs. 8 and 9). The skeleton of the β‐tetrapeptide H‐(R)β3hVal‐(R)β2hVal‐(R)β3hAla‐(S)β3hPhe‐OH ( 4a ) is proposed as a novel, very simple backbone structure for mimicking α‐peptidic hairpin turns. |
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Keywords: | Peptides Amides, α ‐fluoro‐ 314‐Helices Hairpin turn Stereoelectronic effect |
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