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

Conditions: temp:6.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of Boc-D-serine methyl ester (9.59 g, 43.8 mmol) in dichloromethane (100 ml) was stirred at −10° C. during the addition of 4-(dimethylamino)pyridine (270 mg, 2.19 mmol), triethylamine hydrochloride (4.19 g, 43.8 mmol) and tosyl chloride (8.35 g, 43.8 mmol). Triethylamine (6.10 ml, 43.8 mmol) was added dropwise at −10° C. over 35 minutes and the resultant slurry was allowed to stand at 6° C. overnight. The reaction mixture was poured into a mixture of ice (35 g), water (35 ml) and 2N hydrochloric acid (20 ml). The aqueous phase was extracted with dichloromethane (35 ml) and the combined organic solutions washed with brine (2*25 ml), dried (anhydrous magnesium sulfate) and concentrated in vacuo to a pale yellow oil. The oil was dissolved in diethyl ether (100 ml) and cooled to 6° C. Once crystallisation started, petrol ether (75 ml) was added in five portions over two hours, and crystallisation was allowed to proceed at 6° C. overnight to give 2-tert-butoxycarbonylamino-3-(toluene-4-sulfonyloxy)-propionic acid methyl ester (10.98 g, 67%). The aqueous phase was extracted with dichloromethane (35 ml) the combined organic solutions washed with brine (2*25 ml) dried (anhydrous magnesium sulfate) concentrated in vacuo to a pale yellow oil The oil was dissolved in diethyl ether (100 ml) Once crystallisation petrol ether (75 ml) was added in five portions over two hours crystallisation to proceed at 6° C. overnight

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of methyl (2R)-2-{[(tert-butoxy)carbonyl]amino}-3-hydroxypropanoate (22 g, 0.1 mol), 2,2-dimethoxypropane (20.8 g, 0.2 mol) and 4-methylbenzene-1-sulfonic acid (0.5 g) in toluene was heated with stirring at 110° C. overnight. The solvent was removed under reduced pressure. The residue was treated with ethyl acetate, washed with water and brine. The organic layer was dried over sodium sulfate, concentrated under reduced pressure. The residue distilled at 0.6 mbar to give 16.5 g of 3-tert-butyl 4-methyl (4R)-2,2-dimethyl-1,3-oxazolidine-3,4-dicarboxylate (yield was 63.6%) as an amber oil. The solvent was removed under reduced pressure The residue was treated with ethyl acetate washed with water and brine The organic layer was dried over sodium sulfate concentrated under reduced pressure The residue distilled at 0.6 mbar

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

Procedure: To a 2 L three neck flask fitted with a magnetic stirbar, under argon, was added CH2Cl2 (500 mL), PPTs (pyridinium-p-toluene sulfonate) (2 g, 0.008 mol). After dissolving the PPTs by stirring, N-(tert-butoxycarbonyl)-D-serine methyl ester 1 (97.9 g, 0.446 mol) was added to give a clear yellow solution. DHP (3,4-dihydro-2H-pyran) (105 mL, 1.16 mol) was added in one portion. The clear yellow solution was stirred at room temperature over 60 hr to give a slightly cloudy yellow mixture. The mixture was evaporated to give an off-white solid. Ethyl acetate (650 mL) was added to the residue and stirred for 20 minutes to dissolve. The solution was washed with 1.2M HCl (1×500 mL) to pH 4, sat. NaHCO3 (1×600 mL plus 1λ300 mL) to pH 7, brine (1×500 mL), dried over MgSO4 (20 g), filtered and concentrated under reduced pressure to give 129 g (96%) of product 2 as a waxy white solid. 1H NMR (60 MHz, CDCl3) δ 5.2-5.7 (br m, 1H), 3.4-4.8 (m, 9H), 1.4-1.8 (m, 15H). to give a clear yellow solution The clear yellow solution was stirred at room temperature over 60 hr to give a slightly cloudy yellow mixture The mixture was evaporated to give an off-white solid stirred for 20 minutes to dissolve The solution was washed with 1.2M HCl (1×500 mL) to pH 4, sat. NaHCO3 (1×600 mL plus 1λ300 mL) to pH 7, brine (1×500 mL) dried over MgSO4 (20 g) filtered concentrated under reduced pressure

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

Procedure: To a 2 L three neck flask fitted with a magnetic stirbar, under argon, was added CH2Cl2 (500 mL), PPTs (pyridinium-p-toluene sulfonate) (2 g, 0.008 mol). After dissolving the PPTs by stirring, N-(tert-butoxycarbonyl)-D-serine methyl ester 1 (97.9 g, 0.446 mol) was added to give a clear yellow solution. DHP (3,4-dihydro-2H-pyran) (105 mL, 1.16 mol) was added in one portion. The clear yellow solution was stirred at room temperature over 60 hr to give a slightly cloudy yellow mixture. The mixture was evaporated to give an off-white solid. Ethyl acetate (650 mL) was added to the residue and stirred for 20 minutes to dissolve. The solution was washed with 1.2M HCl (1×500 mL) to pH 4, sat. NaHCO3 (1×600 mL plus 1λ300 mL) to pH 7, brine (1×500 mL), dried over MgSO4 (20 g), filtered and concentrated under reduced pressure to give 129 g (96%) of product 2 as a waxy white solid. 1H NMR (60 MHz, CDCl3) δ 5.2-5.7 (br m, 1H), 3.4-4.8 (m, 9H), 1.4-1.8 (m, 15H). to give a clear yellow solution The clear yellow solution was stirred at room temperature over 60 hr to give a slightly cloudy yellow mixture The mixture was evaporated to give an off-white solid stirred for 20 minutes to dissolve The solution was washed with 1.2M HCl (1×500 mL) to pH 4, sat. NaHCO3 (1×600 mL plus 1λ300 mL) to pH 7, brine (1×500 mL) dried over MgSO4 (20 g) filtered concentrated under reduced pressure

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

Procedure: To a solution of (R)-methyl 2-(tert-butoxycarbonylamino)-3-hydroxypropanoate (27.5 g, 0.126 mol) in DMF (250 mL) was added imidazole (25.7 g, 0.378 mol), followed by TBSCl (20.9 g, 0.139 mol) and the reaction mixture stirred for 4 h. The solvents were removed in vacuo and dissolved in EtOAc (300 mL). The solution was washed with saturated NH4Cl (2×100 mL), then with saturated NaHCO3 (100 mL), and brine (100 mL). The organic layer was then dried, filtered, and solvent removed in vacuo to give (R)-methyl 2,2,3,3,10,10-hexamethyl-8-oxo-4,9-dioxa-7-aza-3-silaundecane-6-carboxylate (40 g, yield 95%) as an oil that was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 5.34 (brs, 1H), 4.35 (m, 1H), 4.05 (dd, J=13.2, 3.6 Hz, 1H), 3.82 (dd, J=14, 4.4 Hz, 1H), 1.45 (s, 9H), 3.73 (s, 3H), 0.86 (s, 9H), 0.02 (s, 6H). The solvents were removed in vacuo dissolved in EtOAc (300 mL) The solution was washed with saturated NH4Cl (2×100 mL) The organic layer was then dried filtered solvent removed in vacuo

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

Procedure: To a solution of (R)-methyl 2-(tert-butoxycarbonylamino)-3-hydroxypropanoate (27.5 g, 0.126 mol) in DMF (250 mL) was added imidazole (25.7 g, 0.378 mol), followed by TBSCl (20.9 g, 0.139 mol) and the reaction mixture stirred for 4 h. The solvents were removed in vacuo and dissolved in EtOAc (300 mL). The solution was washed with saturated NH4Cl (2×100 mL), then with saturated NaHCO3 (100 mL), and brine (100 mL). The organic layer was then dried, filtered, and solvent removed in vacuo to give (R)-methyl 2,2,3,3,10,10-hexamethyl-8-oxo-4,9-dioxa-7-aza-3-silaundecane-6-carboxylate (40 g, yield 95%) as an oil that was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 5.34 (brs, 1H), 4.35 (m, 1H), 4.05 (dd, J=13.2, 3.6 Hz, 1H), 3.82 (dd, J=14, 4.4 Hz, 1H), 1.45 (s, 9H), 3.73 (s, 3H), 0.86 (s, 9H), 0.02 (s, 6H). The solvents were removed in vacuo dissolved in EtOAc (300 mL) The solution was washed with saturated NH4Cl (2×100 mL) The organic layer was then dried filtered solvent removed in vacuo

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

Procedure: (R)-2-tert-Butoxycarbonylamino-3-hydroxy-propionic acid methyl ester (2.2 mg, 10 mmol) was dissolved in THF (20 ml). Imidazole (818 mg, 12 mmol) and TBDPS chloride (2.9 ml, 11 mmol) were added. The mixture was stirred at rt overnight. The mixture was then partitioned between CH2Cl2 and water (30 ml/30 ml). The organic layer was concentrated and the residue was purified by column chromatography (6/1, Hexanes/EtOAc) to give (R)-2-tert-butoxycarbonylamino-3-(tert-butyl-diphenyl-silanyloxy)-propionic acid methyl ester (3.3 g, 72%). The mixture was then partitioned between CH2Cl2 and water (30 ml/30 ml) The organic layer was concentrated the residue was purified by column chromatography (6/1, Hexanes/EtOAc)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of methyl (2R)-2-{[(tert-butoxy)carbonyl]amino}-3-hydroxypropanoate (22 g, 0.1 mol), 2,2-dimethoxypropane (20.8 g, 0.2 mol) and 4-methylbenzene-1-sulfonic acid (0.5 g) in toluene was heated with stirring at 110° C. overnight. The solvent was removed under reduced pressure. The residue was treated with ethyl acetate, washed with water and brine. The organic layer was dried over sodium sulfate, concentrated under reduced pressure. The residue distilled at 0.6 mbar to give 16.5 g of 3-tert-butyl 4-methyl (4R)-2,2-dimethyl-1,3-oxazolidine-3,4-dicarboxylate (yield was 63.6%) as an amber oil. The solvent was removed under reduced pressure The residue was treated with ethyl acetate washed with water and brine The organic layer was dried over sodium sulfate concentrated under reduced pressure The residue distilled at 0.6 mbar

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

Procedure: To a 2 L three neck flask fitted with a magnetic stirbar, under argon, was added CH2Cl2 (500 mL), PPTs (pyridinium-p-toluene sulfonate) (2 g, 0.008 mol). After dissolving the PPTs by stirring, N-(tert-butoxycarbonyl)-D-serine methyl ester 1 (97.9 g, 0.446 mol) was added to give a clear yellow solution. DHP (3,4-dihydro-2H-pyran) (105 mL, 1.16 mol) was added in one portion. The clear yellow solution was stirred at room temperature over 60 hr to give a slightly cloudy yellow mixture. The mixture was evaporated to give an off-white solid. Ethyl acetate (650 mL) was added to the residue and stirred for 20 minutes to dissolve. The solution was washed with 1.2M HCl (1×500 mL) to pH 4, sat. NaHCO3 (1×600 mL plus 1λ300 mL) to pH 7, brine (1×500 mL), dried over MgSO4 (20 g), filtered and concentrated under reduced pressure to give 129 g (96%) of product 2 as a waxy white solid. 1H NMR (60 MHz, CDCl3) δ 5.2-5.7 (br m, 1H), 3.4-4.8 (m, 9H), 1.4-1.8 (m, 15H). to give a clear yellow solution The clear yellow solution was stirred at room temperature over 60 hr to give a slightly cloudy yellow mixture The mixture was evaporated to give an off-white solid stirred for 20 minutes to dissolve The solution was washed with 1.2M HCl (1×500 mL) to pH 4, sat. NaHCO3 (1×600 mL plus 1λ300 mL) to pH 7, brine (1×500 mL) dried over MgSO4 (20 g) filtered concentrated under reduced pressure

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

Procedure: To a solution of tert-butyl (R)-1-(methoxycarbonyl)-2-hydroxyethylcarbamate (27.5 g, 0.126 mol) in DMF (250 mL) was added imidazole (25.7 g, 0.378 mol), followed by TBSCl (20.9 g, 0.139 mol) and the reaction mixture was stirred for 4 h. The solvents were removed in vacuo. EtOAc (300 mL) was added and the solution was washed with sat'd aq NH4Cl (2×100 mL), sat'd aq NaHCO3 (100 mL) and brine (100 mL), dried, filtered and evaporated to give tert-butyl (R)-1-(methoxycarbonyl)-2-(t-butyldimethylsilyloxy)ethylcarbamate (40 g, yield 95%) as an oil that was used without further purification. 1H NMR (CDCl3, 400 MHz): δ=0.02 (s, 6H), 0.86 (s, 9H), 1.45 (s, 9H), 3.73 (s, 3H), 3.82 (dd, J=14, 4.4 Hz, 1H), 4.05 (dd, J=13.2, 3.6 Hz, 1H), 4.35 (m, 1H), 5.34 (brs, 1H). The solvents were removed in vacuo EtOAc (300 mL) was added the solution was washed with sat'd aq NH4Cl (2×100 mL) dried filtered evaporated

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

Procedure: To a solution of tert-butyl (R)-1-(methoxycarbonyl)-2-hydroxyethylcarbamate (27.5 g, 0.126 mol) in DMF (250 mL) was added imidazole (25.7 g, 0.378 mol), followed by TBSCl (20.9 g, 0.139 mol) and the reaction mixture was stirred for 4 h. The solvents were removed in vacuo. EtOAc (300 mL) was added and the solution was washed with sat'd aq NH4Cl (2×100 mL), sat'd aq NaHCO3 (100 mL) and brine (100 mL), dried, filtered and evaporated to give tert-butyl (R)-1-(methoxycarbonyl)-2-(t-butyldimethylsilyloxy)ethylcarbamate (40 g, yield 95%) as an oil that was used without further purification. 1H NMR (CDCl3, 400 MHz): δ=0.02 (s, 6H), 0.86 (s, 9H), 1.45 (s, 9H), 3.73 (s, 3H), 3.82 (dd, J=14, 4.4 Hz, 1H), 4.05 (dd, J=13.2, 3.6 Hz, 1H), 4.35 (m, 1H), 5.34 (brs, 1H). The solvents were removed in vacuo EtOAc (300 mL) was added the solution was washed with sat'd aq NH4Cl (2×100 mL) dried filtered evaporated

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

Procedure: To a solution of tert-butyl (R)-1-(methoxycarbonyl)-2-hydroxyethylcarbamate (27.5 g, 0.126 mol) in DMF (250 mL) was added imidazole (25.7 g, 0.378 mol), followed by TBSCl (20.9 g, 0.139 mol) and the reaction mixture was stirred for 4 h. The solvents were removed in vacuo. EtOAc (300 mL) was added and the solution was washed with sat'd aq NH4Cl (2×100 mL), sat'd aq NaHCO3 (100 mL) and brine (100 mL), dried, filtered and evaporated to give tert-butyl (R)-1-(methoxycarbonyl)-2-(t-butyldimethylsilyloxy)ethylcarbamate (40 g, yield 95%) as an oil that was used without further purification. 1H NMR (CDCl3, 400 MHZ): δ=0.02 (s, 6 H), 0.86 (s, 9 H), 1.45 (s, 9 H), 3.73 (s, 3 H), 3.82 (dd, J=14, 4.4 Hz, 1 H), 4.05 (dd, J=13.2, 3.6 Hz, 1H), 4.35 (m, 1 H), 5.34 (brs, 1 H). The solvents were removed in vacuo EtOAc (300 mL) was added the solution was washed with sat'd aq NH4Cl (2×100 mL) dried filtered evaporated