N-[(Phenylmethoxy)carbonyl]-L-serine methyl ester

Clear Waxy Solid

To a solution of methyl L-serinate hydrochloride (1, 1.00 g, 6.43 mmol, 1.00equiv, RF1) in dioxane (5.00 mL, RR2) were added NaHCO3 (1.62 g, 19.3mmol, 3.00 equiv, RR3) in H2O (25.7 mL, RR3) and Cbz-Cl (1.10 mL, 7.72mmol, 1.20 equiv, RR1) in dioxane (15.0 mL, RR1) diluted with dioxane (4.20mL, RR4) and transferred to RF1 at 25 °C. After being stirred at the sametemperature for 5 h, the reaction mixture (RF1) was quenched with 1 M HCl aq.(RS2) and the aqueous layer was extracted with two portions of ethyl acetate(RS1). The combined organic layer was washed with 10percent NaCl aq. (RS3), dried over Na2SO4 (DT2), filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (50percent ethyl acetate in hexane)to give methyl ((benzyloxy)carbonyl)-L-serinate (1.50 g, 5.92 mmol, 92percent) as acolorless oil.2-Benzyloxycarbonylamino-3-hydroxy-propionic acid methyl esterTo a mixture of L-serine methyl ester hydrochloride (1, 88 g, 12.0 mmol) in EtOAc (45 mL) at OEXAMPLE 7 To a stirring solution of MM (16 g, 103 mmol) in water/1 , 4 dioxane (130 mL/65 mL) were added added NaAdapting the procedure of Chhabra et al., 4 to aflame-dried 250 mL round bottom flask containing Cbz-Serine-OH 8 (12.0 g, 50.0 mmol, 1.00 equiv) and K2CO3(7.60 g, 55.0 mmol, 1.10 equiv) in DMF (85 mL, 0.60 M) at 0 °C was added methyl iodide (6.20 mL, 100 mmol, 2.00 equiv) over 30 minutes. The reaction was allowed to warm slowly to room temperature and stirred overnightThe reaction mixture was diluted with EtOAc (500 mL) and washed with a 1:4 mixture of saturated aqueousNaCl:H2O (2 x 100 mL). The combined aqueous washes were back extracted with EtOAc (2 x 150 mL). Thecombined organic extracts were washed sequentially with H2O (2 x 200 mL), saturated aqueous NaCl (2 x 200 mL), 5percent aqueous (w/v) LiCl (2 x 200 mL), and again saturated aqueous NaCl (1 x 200 mL). The combined aqueouswashes were further back-extracted with Et2O (1 x 200 mL), and the combined organics were dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound as a viscous, colorless oil (13.0 g, 99percent) that wasused without further purification (Note: The crude material contained residual DMF). TLC: Rf = 0.17 (40percentEtOAc/hexanes; UV/KMnO4); 1H NMR (600 MHz, CDCl3) δ 7.40–7.30 (m, 5H), 5.79–5.49 (m, 1H), 5.13 (s, 2H), 4.50–4.40 (m, 1H), 4.05–3.98 (m, 1H), 3.96–3.90 (m, 1H), 3.79 (s, 3H), 2.07 (t, J = 6.2 Hz, 1H); 13C NMR (151MHz, CDCl3) δ 171.0, 156.3, 136.2, 128.7, 128.4, 128.3, 67.4, 63.6, 56.2, 53.0. The spectra were in close agreementwith the literature.4 IR (FT-ATR, neat, cm-1): 3362, 2654, 1699, 1519, 1454, 1438, 1209, 1057, 976, 911, 750, 697;HRMS (ESI) m/z for [M+Na]+ C12H15NO5Na requires 276.0848, observed 276.0850; [α]D20 +8.3 (c = 1.0, CHCl3).General procedure: A solution of N-benzyloxycarbonyl-L-amino acid S5 (7.9 mmol) in DMF (20 ml) was added methyliodide (1.1 g, 7.9 mmol) and potassium carbonate (1.2 g, 8.7 mmol). The reaction mixture waskept at room temperature for 3 hours. The methylated products were purified by column chromatographyin the yields of 50percent (1.0 g, colorless-oil) for serine and 92percent (1.9 g, white-solid) for threonine.The methylated amino acid (4.0 mmol) in DMF (10 ml) was mixed with TBDPSCl (2.2 g, 7.9mmol), imidazole (810 mg, 11.9 mmol) and catalytic amount of DMAP. The reaction was processedat 45 °C for 7 hours. The desired products were purified by column chromatography in theyields of 90percent (1.7 g, colorless-oil) for serine and 90percent (1.8 g, white-solid) for threonine. The silylproduct (500 mg, 1.0 mmol) in DMF (1 ml) was reacted with 15percent NaOH (5 ml) for 2 hours. Thereaction mixture was quenching by 1 N HCl(aq) and 6 was extracted by ethyl acetate. The desiredamino acid 6 was obtained after removal of ethyl acetate in the quantitative yields (470 mg, white-solid for serine; 486 mg, colorless-oil for threonine).To a stirring solution of compound 2S-AG (40 g, 0.33 mol) in 1, 4-dioxane (300 mL) and water (100 mL) was added aTo a slurry of L-serine (10.5 g, 100 mmol) in H2O (100 mL), NaHCO3 (21.0 g, 250 mmol), and THF (50 mL) were added successively at 0 °C with cooling of the reaction vessel in an ice-water bath. The mixture was stirred for 30 min, benzyl chloroformate (15.5 mL, 110 mmol) was added dropwise at 0 °C. The ice-water bath was then removed, and the mixture was stirred for 4 h at r.t. The resulting mixture was washed with Et2O (2 × 50 mL) and acidified to pH 2 with aq 3 M HCl. The obtained solution was extractedwith EtOAc (1 × 100 mL and 3 × 50 mL). The combined organicphase was washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was dissolved in MeOH (150 mL), and SOCl2 (8.5 mL, 117 mmol) was then added dropwise to the solution at 0 °C under an N2 atmosphere. The mixture wasstirred for 10 min at 0 °C, the ice-water bath was then removed, and the mixture was stirred overnight at r.t. The resulting solution wasthen concentrated under reduced pressure, dissolved in Et2O (150mL), washed with cold sat. NaHCO3, dried (Na2SO4), filtered, and concentrated under reduced pressure. The obtained crude material was purified by column chromatography (silica gel, hexane–EtOAc, 1:1 to 1:3) to give the product (16.8 g, 66 mmol, 66percent).

N-[(Phenylmethoxy)carbonyl]-L-serine Methyl Ester is used to inhibit the activity of Mycobacterium tuberculosis in studies. Also used in the synthesis of pyrazinecarboxamide-based compounds acting as inhibitors of diacylglycerol acetyltransferases regarding treatment of obesity.