methyl (2S)-3-hydroxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Commercially available N-tert-butoxycarbonyl-serine methyl ester (2.0 g, 9.122 mmol), 2,2-dimethoxypropane (1.9 g, 18.24 mmol), and pyridinium-p-toluene sulfonate (26 mg, 137 μmol) were dissolved in benzene (29 ml) and heated under reflux for 15 hours. A saturated sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with diethylether; the organic layer was subsequently washed with a saturated sodium chloride solution. The washed product was then dried over anhydrous magnesium sulfate and filtered, and the filtrate was subsequently concentrated. The resulting concentrate was purified by silica gel column chromatography to produce 3-tert-butyl 4-methyl 2,2-dimethyloxazolidine-3,4-dicarboxylate (2.78 g, 91% yield). heated under reflux for 15 hours the mixture was extracted with diethylether the organic layer was subsequently washed with a saturated sodium chloride solution The washed product was then dried over anhydrous magnesium sulfate filtered the filtrate was subsequently concentrated The resulting concentrate was purified by silica gel column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: At room temperature, imidazole (6.43 g) was added to a solution of N-(t-butoxycarbonyl)-L-serine methyl ester (13.8 g) in N,N-dimethylformamide (140 ml), followed by the addition of t-butyldiphenylsilyl chloride (19.7 ml) at 0° C. The resulting mixture was stirred at room temperature for 39 hours. Ethyl acetate (200 ml) and water (600 ml) were added to the reaction mixture to cause separation. The water layer was extracted with ethyl acetate (100 ml). The organic layers were combined, washed with saturated aqueous NaCl solution (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was dissolved in tetrahydrofuran (100 ml) and methanol (100 ml) without purification, followed by the addition of sodium borohydride (7.20 g) in portions at 0° C. After stirring at 0° C. for 2 hours and then at room temperature for 1 hour, ethyl acetate (100 ml), an aqueous saturated solution of ammonium chloride (300 ml) and water (300 ml) were added to the reaction mixture to cause separation. The water layer was extracted with ethyl acetate (100 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by chromatography on a silica gel column (500 g of silica gel, hexane:ethyl acetate=10:1˜1:1), whereby the title compound (24.9 g) was obtained as a white solid. separation The water layer was extracted with ethyl acetate (100 ml) washed with saturated aqueous NaCl solution (100 ml) dried over anhydrous sodium sulfate concentrated under reduced pressure The residue thus obtained methanol (100 ml) without purification followed by the addition of sodium borohydride (7.20 g) in portions at 0° C After stirring at 0° C. for 2 hours at room temperature for 1 hour ethyl acetate (100 ml), an aqueous saturated solution of ammonium chloride (300 ml) and water (300 ml) were added to the reaction mixture separation The water layer was extracted with ethyl acetate (100 ml) dried over anhydrous sodium sulfate concentrated under reduced pressure The residue thus obtained was purified by chromatography on a silica gel column (500 g of silica gel, hexane:ethyl acetate=10:1˜1:1), whereby the title compound (24.9 g) was obtained as a white solid

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of N-(tert-butoxycarbonyl)-L-serine methyl ester (25.0 g, 114 mmol) in DCM (570 mL) was cooled to −50° C. Pyridine (23.0 mL, 285 mmol) was added. CBZ-Cl (18.9 mL, 125 mmol) was added dropwise over 1 hour. The reaction mixture was warmed to ambient temperature and stirred overnight. The reaction mixture was then diluted with DCM, washed with 10% citric acid and brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5:1 hexanes/EtOAc) to give (S)-methyl 3-(benzyloxycarbonyloxy)-2-(tert-butoxycarbonylamino)propanoate (36.0 g, 89%). washed with 10% citric acid and brine dried concentrated under reduced pressure The residue was purified by flash chromatography on silica gel (5:1 hexanes/EtOAc)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of methyl N-(tert-butoxycarbonyl)-L-serinate (prepared according to the reported procedure: Bioorg. Med. Chem. 2007, 15, 2860-2867, 10.0 g, 64.27 mmol) in dichloromethane (100 mL), p-toluenesulfonic acid (0.24 g, 1.28 mmol) and 3,4-dihydro-1H-pyran (8.8 mL, 96.67 mmol) were added and the mixture was stirred at the room temperature for 16 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic layers were washed with water (2×50 mL), brine solution (50 mL) and dried over sodium sulfate. Removal of solvent under vacuum and also high vacuum to remove excess 3,4-dihydro-1H-pyran. The residue was dissolved in ethyl acetate (10 mL) and pet. ether (100 mL) was added over it was stirred for 10 minutes. The solid obtained was filtered and washed with pet. ether (50 mL). Yield: 12.0 g (78%). 1H NMR (400 MHz, DMSO-d6) δ: 1.33-1.34 (m, 1H), 1.39 (s, 9H), 1.41-1.68 (m, 6H), 3.41-3.45 (m, 1H), 3.55-3.59 (m, 1H), 3.61 (s, 3H), 3.81-3.84 (m, 1H), 4.23-4.28 (m, 1H), 4.58 (br s, 1H), 7.15 (d, 1H). The reaction mixture was quenched with saturated sodium bicarbonate solution (50 mL) extracted with dichloromethane (3×50 mL) The combined organic layers were washed with water (2×50 mL), brine solution (50 mL) dried over sodium sulfate Removal of solvent under vacuum and also high vacuum to remove excess 3,4-dihydro-1H-pyran The residue was dissolved in ethyl acetate (10 mL) pet. ether (100 mL) was added over it was stirred for 10 minutes The solid obtained was filtered washed with pet. ether (50 mL)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Boc-Ser-OME, 110 mg (0.5 mmol), and 87 mg (0.5 mmol) of 3-aminobenzenesulfonic acid were dissolved in 1 ml of pyridine, and 50 mg of triphosgene was added to the solution. The mixture was stirred at room temperature for 2 hours and the solvent was then distilled off. The resulting residue was purified according to the purification step A to give the crude product of the protected title compound. The crude product obtained was dissolved in 1 ml of methylene chloride and 1 ml of trifluoroacetic acid. The solution was stirred for 30 minutes at room temperature. After the solvent was distilled off, the mixture was purified in accordance with the purification step A to give the title compound. the solvent was then distilled off The resulting residue was purified according to the purification step A

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of methyl N-(tert-butoxycarbonyl)-L-serinate (prepared according to the reported procedure: Bioorg. Med. Chem. 2007, 15, 2860-2867, 10.0 g, 64.27 mmol) in dichloromethane (100 mL), p-toluenesulfonic acid (0.24 g, 1.28 mmol) and 3,4-dihydro-1H-pyran (8.8 mL, 96.67 mmol) were added and the mixture was stirred at the room temperature for 16 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic layers were washed with water (2×50 mL), brine solution (50 mL) and dried over sodium sulfate. Removal of solvent under vacuum and also high vacuum to remove excess 3,4-dihydro-1H-pyran. The residue was dissolved in ethyl acetate (10 mL) and pet. ether (100 mL) was added over it was stirred for 10 minutes. The solid obtained was filtered and washed with pet. ether (50 mL). Yield: 12.0 g (78%). 1H NMR (400 MHz, DMSO-d6) δ: 1.33-1.34 (m, 1H), 1.39 (s, 9H), 1.41-1.68 (m, 6H), 3.41-3.45 (m, 1H), 3.55-3.59 (m, 1H), 3.61 (s, 3H), 3.81-3.84 (m, 1H), 4.23-4.28 (m, 1H), 4.58 (br s, 1H), 7.15 (d, 1H). The reaction mixture was quenched with saturated sodium bicarbonate solution (50 mL) extracted with dichloromethane (3×50 mL) The combined organic layers were washed with water (2×50 mL), brine solution (50 mL) dried over sodium sulfate Removal of solvent under vacuum and also high vacuum to remove excess 3,4-dihydro-1H-pyran The residue was dissolved in ethyl acetate (10 mL) pet. ether (100 mL) was added over it was stirred for 10 minutes The solid obtained was filtered washed with pet. ether (50 mL)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of triphenylphosphine (4.55 g, 17.4 mmol) and hexachloroethane (3.9 g, 16.5 mmol) in 1,2-dichloroethane (18 mL) prepared at 0° C. was added via cannula into a flask containing a solution of methyl N-(tert-butoxycarbonyl)-L-serinate (3.2 g, 14.6 mmol) in 1,2-dichloroethane DCE (40 mL), kept at 0° C. under N2 atmosphere. After the addition was completed, the reaction mixture was further stirred at room temperature for 2 h, diluted with DCM, washed with sat NaHCO3, dried over MgSO4, filtered and concentrated. Purification made through chromatographic column of silicagel eluted with 10% to 50% EtOAc in hexane for 30 min, to afford 2.13 g (61% yield) of title compound as white crystals. MS: m/z=260.0 (MNa+). was added via cannula into a flask kept at 0° C. under N2 atmosphere After the addition washed dried over MgSO4 filtered concentrated Purification of silicagel eluted with 10% to 50% EtOAc in hexane for 30 min

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of triphenylphosphine (65.8 g, 0.251 mol)) and hexachloroethane (59.4 g, 0.251 mol) in dichloromethane (850 mL) was added in one portion to a solution of N-Boc-serine methyl ester (50 g, 0.228 mol) in dichloromethane (170 mL) under argon atmosphere. The reaction mixture was stirred at room temperature for 2 h and then the reaction was quenched with a saturated solution of NaHCO3 (150 mL). The organic product was extracted with dichloromethane (2×300 mL) and the combined organic layers was washed with brine (300 mL) and dried over anhydrous sodium sulphate. The solution was concentrated under reduced pressure and then triturated with Et2O (500 mL). After filtration and evaporation of the solvent, the crude product was purified by chromatography on a silica column eluted with 6-8% EtOAc in pet ether) which gave the title compound (42 g, 78%). the reaction was quenched with a saturated solution of NaHCO3 (150 mL) The organic product was extracted with dichloromethane (2×300 mL) the combined organic layers was washed with brine (300 mL) dried over anhydrous sodium sulphate The solution was concentrated under reduced pressure triturated with Et2O (500 mL) After filtration and evaporation of the solvent the crude product was purified by chromatography on a silica column eluted with 6-8% EtOAc in pet ether) which

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of triphenylphosphine (65.8 g, 0.251 mol)) and hexachloroethane (59.4 g, 0.251 mol) in dichloromethane (850 mL) was added in one portion to a solution of N-Boc-serine methyl ester (50 g, 0.228 mol) in dichloromethane (170 mL) under argon atmosphere. The reaction mixture was stirred at room temperature for 2 h and then the reaction was quenched with a saturated solution of NaHCO3 (150 mL). The organic product was extracted with dichloromethane (2×300 mL) and the combined organic layers was washed with brine (300 mL) and dried over anhydrous sodium sulphate. The solution was concentrated under reduced pressure and then triturated with Et2O (500 mL). After filtration and evaporation of the solvent, the crude product was purified by chromatography on a silica column eluted with 6-8% EtOAc in pet. ether) which gave the title compound (42 g, 78%). the reaction was quenched with a saturated solution of NaHCO3 (150 mL) The organic product was extracted with dichloromethane (2×300 mL) the combined organic layers was washed with brine (300 mL) dried over anhydrous sodium sulphate The solution was concentrated under reduced pressure triturated with Et2O (500 mL) After filtration and evaporation of the solvent the crude product was purified by chromatography on a silica column eluted with 6-8% EtOAc in pet. ether) which

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of triphenylphosphine (65.8 g, 0.251 mol)) and hexachloroethane (59.4 g, 0.251 mol) in dichloromethane (850 mL) was added in one portion to a solution of N-Boc-serine methyl ester (50 g, 0.228 mol) in dichloromethane (170 mL) under argon atmosphere. The reaction mixture was stirred at room temperature for 2 h and then the reaction was quenched with a saturated solution of NaHCO3 (150 mL). The organic product was extracted with dichloromethane (2×300 mL) and the combined organic layers was washed with brine (300 mL) and dried over anhydrous sodium sulphate. The solution was concentrated under reduced pressure and then triturated with Et2O (500 mL). After filtration and evaporation of the solvent, the crude product was purified by chromatography on a silica column eluted with 6-8% EtOAc in pet. ether) which gave the title compound (42 g, 78%). the reaction was quenched with a saturated solution of NaHCO3 (150 mL) The organic product was extracted with dichloromethane (2×300 mL) the combined organic layers was washed with brine (300 mL) dried over anhydrous sodium sulphate The solution was concentrated under reduced pressure triturated with Et2O (500 mL) After filtration and evaporation of the solvent the crude product was purified by chromatography on a silica column eluted with 6-8% EtOAc in pet. ether) which

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Compound 2 (285 mg, 1.15 mmol), (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-hydroxypropanoate (251 mg, 1.15 mmol) and triphenylphosphine (452 mg, 1.72 mmol) were dissolved in 11 mL of anhydrous THF, and stirred at room temperature for 5 min. DIAD (338 μL, 1.72 mmol) was added to the reaction mixture and then stirred overnight at 45° C. The reaction mixture was diluted with ethyl acetate and washed with sat'd NH4Cl aqueous solution. The organic layer was collected, dried over anhydrous Na2SO4, filtered, concentrated and purified by silica column chromatography (30% ethyl acetate in hexanes) to afford compound 21d (99.5%, 517 mg) as a white solid. stirred overnight at 45° C washed with sat'd NH4Cl aqueous solution The organic layer was collected dried over anhydrous Na2SO4 filtered concentrated purified by silica column chromatography (30% ethyl acetate in hexanes)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Commercially available N-tert-butoxycarbonyl-serine methyl ester (2.0 g, 9.122 mmol), 2,2-dimethoxypropane (1.9 g, 18.24 mmol), and pyridinium-p-toluene sulfonate (26 mg, 137 μmol) were dissolved in benzene (29 ml) and heated under reflux for 15 hours. A saturated sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with diethylether; the organic layer was subsequently washed with a saturated sodium chloride solution. The washed product was then dried over anhydrous magnesium sulfate and filtered, and the filtrate was subsequently concentrated. The resulting concentrate was purified by silica gel column chromatography to produce 3-tert-butyl 4-methyl 2,2-dimethyloxazolidine-3,4-dicarboxylate (2.78 g, 91% yield). heated under reflux for 15 hours the mixture was extracted with diethylether the organic layer was subsequently washed with a saturated sodium chloride solution The washed product was then dried over anhydrous magnesium sulfate filtered the filtrate was subsequently concentrated The resulting concentrate was purified by silica gel column chromatography