Fmoc-N-methyl-L-phenylalanine

Fmoc-N-Me-Phe-OH is a peptide inhibitor of Malaria Parasite[1].

The Fmoc-phenylalaninyloxazolidinone (4.60g, 11.6mmol) was dissolved in chloroform (58mL). Trifluoroacetic acid (2.68mL, 34.8equiv) and triethylsilane (5.56mL, 34.8equiv) were added to the solution. The reaction mixture was stirred at room temperature until the reaction was complete (24–72h). The solution was concentrated and partitioned between ether and saturated sodium bicarbonate solution. The combined aqueous phase was acidified with 5M hydrochloric acid to pH 2 and extracted with ethyl acetate. The desired organic phase was then dried (MgSOTo a solution of Fmoc-l-Phe 12 (740 mg, 1.91 mmol) in toluene (40 ml) was added 75percent paraformaldehyde (395 mg) and p-toluenesulfonic acid monohydrate (44 mg, 0.23 mmol) and refluxed for 30 min with azeotropic water removal. After cooling to room temperature, the organic layer was washed with 1 N NaHCOGeneral procedure: Paraformaldehyde (1.92 g, 64.0 mmol) and p-toluenesulfonic acid (0.1920 g, 0.12 mmol) were added to a solution of Fmoc-Ala-OH (3.00 g, 9.6 mmol) in toluene (150 mL). The mixture was refluxed for 3 h with Dean–Stark apparatus. After cooled to room temperature, the resultant mixture was washed with saturated NaHCOTo a solution of S1 (2.51 g, 6.28 mmol) in CHCl3 (42 ml) were added Et3SiH (4.0 ml, 25.0 mmol) and TFA (38.5 ml, 503 mmol) and the mixture was stirred for 47 h. The mixture was azeotroped dry by the addition of toluene followed by evaporation. The residue was purified with column chromatography (CHCl3:MeOH = 98:2 v/v) to give S2 (2.81 g, 7.00 mmol, >99percent) as a white solid.The Fmoc-phenylalaninyloxazolidinone (4.60g, 11.6mmol) was dissolved in chloroform (58mL). Trifluoroacetic acid (2.68mL, 34.8equiv) and triethylsilane (5.56mL, 34.8equiv) were added to the solution. The reaction mixture was stirred at room temperature until the reaction was complete (24'72h). The solution was concentrated and partitioned between ether and saturated sodium bicarbonate solution. The combined aqueous phase was acidified with 5M hydrochloric acid to pH 2 and extracted with ethyl acetate. The desired organic phase was then dried (MgSO4) and concentrated to give the product as a dark yellow oil. The crude product was dissolved in dichloromethane and evaporated repeatedly to give Fmoc-N-methylphenylalanine as a brown solid (3.73g, 80percent): mp 106'107°C; LRMS (ESI) m/z [M+H]+ 402.1 (100percent); 1H NMR (300MHz, CDCl3) deltaH (ppm) (rotamers) 7.74 (2H, d, J=7.5Hz, ArH), 7.49 (1H, d, J=7.8Hz, ArH), 7.43 (1H, t, J=6.9Hz, ArH), 7.37 (2H, t, J=7.5Hz, ArH), 7.25'7.21 (6H, m, ArH), 6.95 (1H, d, J=6.3Hz, ArH), 4.89 (1H, dd, J=5.1, 11.1Hz, NCHCOOH), 4.59'4.53 (1H, m, (Ar)2CHCH2), 4.38 (2H, d, J=14.4Hz, CHCH2O), 3.41'3.35 (1H, m, CHCHHAr), 3.16'3.08 (1H, m, CHCHHAr), 2.77 (3H, s, NCH3), 2.75 (3H, s, NCH3) (1H NMR data was in agreement with that previously described);33 13C NMR (75MHz, CDCl3) deltaC (ppm) 175.5, 156.5, 143.4, 140.9, 136.4, 128.4, 128.3, 127.3, 126.7, 126.5, 124.6, 124.3, 119.6, 67.6, 60.7, 46.7, 34.3, 32.3.To a solution of Fmoc-l-Phe 12 (740 mg, 1.91 mmol) in toluene (40 ml) was added 75percent paraformaldehyde (395 mg) and p-toluenesulfonic acid monohydrate (44 mg, 0.23 mmol) and refluxed for 30 min with azeotropic water removal. After cooling to room temperature, the organic layer was washed with 1 N NaHCO3 aq (2.x.20 ml), dried over Na2SO4, filtered, and concentrated in vacuo to yield oxazolidine 13 as an oil. To a solution of the oxazolidine 13 (970 mg, 2.43 mmol) in CHCl3 (10 ml) was added TFA (10 ml) and Et3SiH (0.55 ml, 3.44 mmol). The reaction mixture was stirred for 16 h at room temperature and concentrated in vacuo. The oil was dissolved in CHCl3 and reconcentrated three times and purified by a silica gel column chromatography (n-hexane/acetone 7:1-->4:1-->2:1-->1:1-->1:2) to yield N-Fmoc-N-methyl-Phe 8 (826 mg, 2.06 mmol, 85percent, 2 steps) as a white powder; Mp 137-138 °C; 1H NMR (400 MHz, CDCl3) (isomer I) deltaH 7.76-6.95 (13H, m), 4.88 (1H, br q) 4.36 (2H, br m) 4.21 (1H, br s), 3.39 (1H, br d), 3.14 (1H, br t), 2.80 (3H, d, J=3.2 Hz); (isomer II) deltaH 7.76-6.95 (13H, m), 4.56 (2H, m), 4.36 (2H, br m), 4.16 (1H, br s), 3.14 (1H, br t), 2.78 (3H, s).General procedure: Paraformaldehyde (1.92 g, 64.0 mmol) and p-toluenesulfonic acid (0.1920 g, 0.12 mmol) were added to a solution of Fmoc-Ala-OH (3.00 g, 9.6 mmol) in toluene (150 mL). The mixture was refluxed for 3 h with Dean'Stark apparatus. After cooled to room temperature, the resultant mixture was washed with saturated NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. After recrystallization with ethylacetate and petroleum ether, the intermediate was obtained without further purification. Trifluoroacetic acid (48.0 mL) and triethylsilane (4.60 mL, 28.8 mmol) were added to a solution of above intermediate in CHCl3 (25 mL). The resultant mixture was stirred at room temperature overnight. After concentration, the residue was dissolved in CH2Cl2 and concentrated again; after repeated for three times, the oil liquid was turned to white solid. Then the white solid was dissolved in diethyl ether, concentrated, washed three times with petroleum ether. The residue was purified by flash-column chromatography on silica gel, to yield the white solid product (2.51 g, 80percent yield).

Molecular Weight:401.5
XLogP3:4.8
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:7
Exact Mass:401.16270821
Monoisotopic Mass:401.16270821
Topological Polar Surface Area:66.8
Heavy Atom Count:30
Complexity:580
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes