| 89% |
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General procedure: Synthesis. Materials. Na-Fmoc-protected amino acids, HBTU and HOBt were purchased from AAPPTEC (Louisville, KY) and from Chem-Impex International Inc. (Wooddale, IL). Trityl resin was purchased from AnaSpec (Fremont, CA). Rink resin was purchased from ChemImpex (Wood Dale, IL). Peptide synthesis solvents, reagents, as well as CH3CN for HPLC were acquired from commercial sources and used without further purification. The synthesis of NPS analogues was performed in part or completely on solid-phase resin method in a stepwise fashion via peptide synthesizer (AAPPTEC Focus XC, AAPPTEC). Na-Fmoc-AA1-OH (AA1: Fmoc-transACHC, Na-Fmoc-(S)-cyanoalanine, Na-Fmoc-(S)-13-tetrazolealanine, Na-Fmoc-N6-Boc-(S)-lysine or N13-Fmoc-(S)-3-amino-3-phenylpropanoic acid was coupled to Rink resin (0.52 meq/g) via peptide coupling or coupled to Trityl resin (0.1 g, 0.9 meq/g) with DIEA (2M in NMP) for 90 mm. The following protected amino acids were then added stepwise Na-Fmoc-AA2-OH (AA2: Fmoc-Gly-OH, Na-Fmoc-N6-Boc-(S)-lysine, Na-Fmoc-N6-Mtt-(S)-lysine or Na-Fmoc-Phe-OH). Each coupling reaction was accomplished using a 3-fold excess of amino acid with HBTU and HOBt (1.5 mL, 0.5M each in DMF) in the presence of DIEA (0.8 mL, 2M in NMP). The Na-Fmoc protecting groups were removed by treating the protected peptide resin with a 20% solution of piperidine in DMF, (lx 5 mm, lx 10 mm); [000157] N13-Fmoc-(R)-3-amino-3-phenylpropanoic acid (250 mg) was coupled to Rink resin (0.52 meq/g) via peptide coupling using an AAPPTEC Focus peptide synthesizer. Rink resin (130 mg) was washed with DMF (5x 10 mL) and the Na-Fmoc protecting group removed with a 20% solution of piperidine in DMF, (lx 5 mi lx 10 mm) followed by DMF wash (3x). The following protected amino acids were then added stepwise Na-Fmoc-AA2-OH (AA2: Na-Fmoc-Gly-OH, NaFmoc-Phe-OH). Each coupling reaction was accomplished using a 3-fold excess of amino acid with HBTU and HOBt (1.5 mL, 0.5M each in DMF) in the presence of DIEA (0.8 mL, 2M in NMP) under nitrogen atmosphere over 45 mm. The Na-Fmoc protecting groups were removed by treating the protected peptide resin with a 20% solution of piperidine in DMF, (lx 5 mi lx 10 mm). The peptide resin was washed three times with DMF and conditioned by shaking with CH2C12 (3 x 10 mm), under nitrogen atmosphere. The peptide resin was washed three times with DMF and then coupled with benzoic acid (3 equivalents) with HBTU and HOBt (1.5 mL, 0.5M each in DMF) in the presence of DIEA (0.8 mL, 2M in NMP) under nitrogen atmosphere over 45 mm. The peptide resin was washed with DCM (3x), and the peptide was released from the resin with TFA / DCM (1:1, 10 mL) over 0.5 h. The resin was removed by filtration and the crude peptide was recovered by precipitation with cold anhydrous ethyl ether and dried in vacuo. The desired product R06039-663 was obtained as a white solid (20 mg, 89%). ?H NMR (300 MHz, DMSO-d6) d ppm 3.04 (d, J=10.55 Hz, 3 H) 3.16 (br. s., 1 H) 3.75 (d, J=5.65 Hz, 2 H) 4.67 (br. s., 1 H) 5.22 (d, J=8.29 Hz, 1 H) 6.81 (br. s., 1 H) 7.09 - 7.56 (m, 14 H) 7.79 (d, J=6.97 Hz, 2 H) 8.29 - 8.45 (m, 2 H) 8.67 (d, J=8.10 Hz, 1 H) ESI MS m/z:Calculated for C27H28N404 472.54, Found 473.3 (M+H) HPLC (Synergy Hydro, 20 mm) tR = 15.63 mm (>98%). |
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