Electrophilic <i>S</i>‐Trifluoromethylation of Cysteine Side Chains in <i>α</i>‐ and <i>β</i>‐Peptides: Isolation of Trifluoro‐methylated <i>Sandostatin</i>^® (Octreotide) Derivatives

Abstract

Abstract The new electrophilic trifluoromethylating 1‐(trifluoromethyl)‐benziodoxole reagents A and B ( Scheme 1 ) have been used to selectively attach CF 3 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 1 H‐, 13 C‐, and 19 F‐NMR spectroscopy, by CD spectroscopy, and by high‐resolution mass spectrometry. The CF 3 groups, thus introduced, may be replaced by H (Na/NH 3 ), an overall Cys/Ala conversion. The importance of trifluoromethylations in medicinal chemistry and possible applications of the method (spin‐labelling, imaging, PET) are discussed.