Electrophilic S‐Trifluoromethylation of Cysteine Side Chains in α‐ and β‐Peptides: Isolation of Trifluoro‐methylated Sandostatin® (Octreotide) Derivatives |
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| Authors: | Stefania Capone Iris Kieltsch Oliver Flögel Gerald Lelais Antonio Togni Dieter Seebach |
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| Institution: | 1. Laboratorium für Organische Chemie, Departement Chemie und Angewandte Biowissenschaften, ETH‐Zürich, H?nggerberg, Wolfgang‐Pauli‐Strasse 10, CH‐8093 Zürich, (phone: +41‐44‐632‐2990;2. fax: +41‐44‐632‐1144);3. Postdoctoral Research Fellow at ETH‐Zürich, 2006–2008, financed by the Swiss National Science Foundation (Project No. 200020‐109065 and 200020‐117586).;4. Laboratorium für Anorganische Chemie, Departement Chemie und Angewandte Biowissenschaften, ETH‐Zürich H?nggerberg, Wolfgang‐Pauli‐Strasse 10, CH‐8093 Zürich, (fax: +41‐44‐632‐1310);5. Part of the Ph.D. Thesis of I.?K., ETH‐Zürich, 2008, Dissertation No. 17990.;6. Postdoctoral Research Fellow at ETH‐Zürich, 2004–2006, financed by the Deutsche Forschungsgemeinschaft (DFG), by the Swiss National Science Foundation (Project No. 200020‐100182), and by Novartis Pharma AG, Basel.;7. Part of the Ph.D. Thesis of G.?L., ETH‐Zürich, 2000–2004, Dissertation No. 15429. |
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| Abstract: | The new electrophilic trifluoromethylating 1‐(trifluoromethyl)‐benziodoxole reagents A and B (Scheme 1) have been used to selectively attach CF3 groups to the S‐atom of cysteine side chains of α‐ and β‐peptides (up to 13‐residues‐long; products 7 – 14 ). Other functional groups in the substrates (amino, amido, carbamate, carboxylate, hydroxy, phenyl) are not attacked by these soft reagents. Depending on the conditions, the indole ring of a Trp residue may also be trifluoromethylated (in the 2‐position). The products are purified by chromatography, and identified by 1H‐, 13C‐, and 19F‐NMR spectroscopy, by CD spectroscopy, and by high‐resolution mass spectrometry. The CF3 groups, thus introduced, may be replaced by H (Na/NH3), an overall Cys/Ala conversion. The importance of trifluoromethylations in medicinal chemistry and possible applications of the method (spin‐labelling, imaging, PET) are discussed. |
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| Keywords: | Electrophilic trifluoromethylation Trifluoromethylation Cysteine Peptides Sandostatin® Somatostatin Post‐translational modifications Octreotide |
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