Fig. 8. Solid-phase peptide synthesis of difluorinated oxytocin.

a About 20% piperidine/DMF, 10 min, double; b 1.5 equiv. fluorinated leucine, 1.5 equiv. HOBt, 1.5 equiv. DIC, minimum DMF, rt, 16 h; c 10% piperidine/DMF, 3 mins, double; d 3 equiv. amino acid, 2.9 equiv. HBTU, 6 equiv. DIPEA, minimum DMF, rt, 1.5 h; e 10% piperidine/DMF, 3 mins, double; f TFA cocktail, global deprotection, rt, 3 h; g GSH/GSSG folding, rt, over-night. Fmoc = fluorenylmethoxycarbonyl, HOBt = hydroxybenzotriazole, DIC = N,N’-diisopropylcarbodiimide, HBTU = N,N,N’,N’-tetramethyl-O-(1H-benzotriazol-1-yl)-uronium hexafluorophosphate, DIPEA = N,N-diisopropylethylamine, GSSG = glutathione disulfide.