5-(1,1-Dimethylethyl) hydrogen L-glutamate

White powder crystal

The synthesis of g-tert-butyl-l-glutamic acid (Glu(OtBu)) NCA was slightly optimized based on existing procedures.21 H-Glu(OtBu)-OH (15.0 g, 73.8 mmol) were thoroughly pestled and dried for 1 h under vacuum in a septum- sealed round bottom flask equipped with a stir-bar. Freshly distilled dried THF (300 ml_) were used to suspend the solid. Freshly distilled triethylamine (20.4 mL, 148 mmol) was added, followed by addition of trimethylsilyl chloride (18.8 mL, 148 mmol). The suspension was stirred for 2 h at room temperature. To remove the precipitated salts, the solution was transferred in a nitrogen gas atmosphere and passed through a ceramic filter (16^10 pm pore size) into a three-necked round-bottomed flask equipped with a stir bar, a condenser, a rubber septum and a glass stopper. The filter residue was extracted twice with THF (50 mL) and extracts were added to the solution. Two gas washing bottles were connected to the condenser outlet and equipped with NaOH (8.86 g (3eq)) dissolved in water (250 mL). After verifying a gas-tight apparatus by observable bubbling in the gas washing bottles due to the nitrogen stream, the nitrogen stream was stopped after purging for an hour. Diphosgene (7.1 mL, 59 mmol) was added to the mixture at room temperature and heated to 50 C during 1 h and to 70 C for 30 min. The reaction was cooled to room temperature under a constant stream of nitrogen introduced via the septum. After room temperature was reached the septum was exchanged to a quick-fit and a stream of nitrogen was bubbled through a glass rod into the solution for (0048) 3 h. The flask was stored overnight at -80C and the residual solvent removed under high vacuum starting at low temperature. The solid residue was redissolved in THF (50 mL) and toluene (50 mL). The solution was precipitated to hexane (600 mL) under instant sonication, the white precipitate was collected by filtration under nitrogen atmosphere and dried under vacuum. (12.0 g, 71 % yield) of fine white powder were obtained and recrystallized twice. 1 H NMR (400 MHz, DMSO-cfe): d [ppm] = 9.07 (s, 1 H, CO-NH-CHR), 4.45 (1 H, ddd, JH, H = 7.6 Hz, 5.6 Hz, 1 .2 Hz, NH-CH-CO), 2.34 (m, 2H, CH2-CH2-CO), 1 .80-2.05 (m, 2H, CH2-CH2-CO), 1 .40 (s, 9H, -0-C(CH3)3). Melting point: 102.5C (measured at 2C/min).A mixture of 2-chlorotrityl chloride resin (30 g, 92 mmol), triethylamine (46.4 g, 458 mmol) and (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-(tert-butoxy)-5-oxopentanoic acid (25.5 g, 60 mmol) in dry dichloromethane (200 mL) was bubbled with N2 at 20C for 8 hours. The mixture was filtered and the resin was washed with dichloromethane (2 x 200 mL), methanol (MeOH) (2 x 200 mL), and dimethyl formamide (2 x 200 mL). The resin was added a solution of piperidine: dimethyl formamide (1:4, 400 mL) and the mixture was bubbled with N2 for 8 minutes and then filtered. This operation was repeated five times to give complete removal of the 9-fluorenylmethyloxycarbonyl (Fmoc) protecting group. The resin was washed with dimethyl formamide (5 x 500 mL) to afford resin bound (S)-2-amino-5-(tert- butoxy)-5-oxopentanoic acid. A mixture of 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)acetic acid (13.38 g, 45.0 mmol), /V, /V-di isopropyl ethyl amine (7.86 mL, 45 mmol), hydroxybenzotriazole (6.89 g, 45 mmol), 2-(6-chloro-lH-benzo[d] [1 , 2, 3]triazol-l -yl)-l , 1 , 3, 3-tetramethylisouronium hexafluorophosphate (V) (18.62 g, 45.0 mmol) in dimethyl formamide (200 mL) was stirred at 20C for 30 min. To the mixture was added the resin bound (5)-2-amino-5-(tert-butoxy)-5-oxopentanoic acid and the resulting mixture was bubbled with N2 at 25 C for 1.5 hours. The mixture was filtered and the resin was washed with dimethyl formamide (4 x 500 mL), and dichloromethane (2 x 500 mL). To the mixture was added 1 % trifluoro acetic acid / dichloromethane (5 x 500 mL) and bubbled with N2 for 5 min. The mixture was filtered and the filtrate was added to saturated solution of NaHC03 (200 mL) directly. The combined mixture was separated, and the organic phase was washed with saturated citric acid water solution (4 x 400 mL) and brine (2 x 300 mL). The final organic solution was dried over Na2S04 (20 g), filtered, concentrated under reduced pressure to afford the title compound (10 g, yield 20%). 'H NMR: (CDCl3, 400 MHz) d 7.75 (d, J = 7.5 Hz, 2H), 7.59 (br d, / = 7.5 Hz, 2H), 7.41 - 7.36 (m, 2H), 7.30 (t, / = 7.0 Hz, 2H), 5.82 (br s, 1H), 4.57 (br d, / = 4.8 Hz, 1H), 4.38 (br d, / = 7.5 Hz, 2H), 4.27 - 4.15 (m, 1H), 4.06 - 3.83 (m, 2H), 2.50 - 2.29 (m, 2H), 2.26 - 2.13 (m, 1H), 2.06 - 2.02 (m, 1H), 1.43 (s, 9H).

Molecular Weight:203.24
XLogP3:-2.4
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:6
Exact Mass:203.11575802
Monoisotopic Mass:203.11575802
Topological Polar Surface Area:89.6
Heavy Atom Count:14
Complexity:219
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes