Fmoc-(R)-3-Amino-3-phenylpropionic acid

white powder

General procedure: DIPEA (2-3 eq.) and Fmoc-OSu (0.9 eq) are added to the amino acid or its hydrochloride (1 eq.) in a 1:1 mixture of acetonitrile/water (20 mL/1 mmol amino acid) and the mixture is stirred for at least 90 min at room temperature. After acidification with 1M HCl, the reaction mixture is extracted withdichloromethane (3x). The combined organic phases are washed with brine, dried with MgSO4, filteredand the solvent is evaporated under reduced pressure to afford the crude Fmoc-protected amino acid. If necessary, the residue is crystallized from dichloromethane/hexane to afford the desired product as a solid.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%).General procedure: 2-Fluorobenzaldehyde (42.3 mg, 0.25 mmol) was first dissolved in a 15 mL conical centrifuge tube with MeOH (330 mL) and the amine (0.25 mmol) was added. The resulting mixture was agitated with an orbital mixer for 30 min and the Fmoc-protected amino acid (0.25 mmol) added to the reaction with CH2Cl2 (170 mL). After stirring for 15 min, the isocyanide (0.25 mmol) was added and the mixture agitated for 72 h. Finally, the solvent was removed under reduced pressure and the crude product dissolved in DMF to be purified by RP-HPLC. The fractions containing the desired product in >95% purity were pooled and freeze dried.

Molecular Weight:387.4
XLogP3:4.1
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:7
Exact Mass:387.14705815
Monoisotopic Mass:387.14705815
Topological Polar Surface Area:75.6
Heavy Atom Count:29
Complexity:551
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes