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

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The N-Boc-serine benzyl ester was brought up in dichloromethane (170 mL) and treated with carbon tetrabromide (26.37 g, 79.51 mmol, 1.2 eq.), and triphenylphosphine (25.20 g, 96.08 mmol, 1.45 eq.) and the solution was stirred at 0° C. for 30 min. The volatiles were then evaporated in vacuo and the residue was triturated with ether (1000 mL). The solid that separated out was filtered off and organic layer was evaporated in vacuo to get the crude product. The crude material was purified by flash chromatography on silica gel to get N-Boc-β-bromoalanine benzyl ester. The volatiles were then evaporated in vacuo the residue was triturated with ether (1000 mL) The solid that separated out was filtered off organic layer was evaporated in vacuo to get the crude product The crude material was purified by flash chromatography on silica gel

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

Procedure: In a round-bottomed flask were placed N-BocSerine (20.0 g, 89.605 mmol, 1 eq.), benzyl bromide (10.76 ml, 90.50 mmol, 1.01 eq.) and cesium carbonate (56.64 g, 173.84 mmol, 1.94 eq.) in DMF (180 mL). The suspension was stirred under nitrogen at room temperature for 2 hrs to overnight. The mixture was partitioned between water and ethyl acetate (1:1, 1000 ml) and aqueous layer was re-extracted with ethyl acetate(2×200 mL). The combined organic layers were washed with water (2×500 mL), saturated sodium chloride, and dried over sodium sulfate. The solvents were removed in vacuo and the crude material purified on silica gel to get N-Boc-serine benzyl ester. In a round-bottomed flask were placed The mixture was partitioned between water and ethyl acetate (1:1, 1000 ml) and aqueous layer was re-extracted with ethyl acetate(2×200 mL) The combined organic layers were washed with water (2×500 mL), saturated sodium chloride dried over sodium sulfate The solvents were removed in vacuo the crude material purified on silica gel

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

Procedure: In a round-bottomed flask were placed N-BocSerine (20.0 g, 89.605 mmol, 1 eq.), benzyl bromide (10.76 ml, 90.50 mmol, 1.01 eq.) and cesium carbonate (56.64 g, 173.84 mmol, 1.94 eq.) in DMF (180 mL). The suspension was stirred under nitrogen at room temperature for 2 hrs to overnight. The mixture was partitioned between water and ethyl acetate (1:1, 1000 ml) and aqueous layer was re-extracted with ethyl acetate(2×200 mL). The combined organic layers were washed with water (2×500 mL), saturated sodium chloride, and dried over sodium sulfate. The solvents were removed in vacuo and the crude material purified on silica gel to get N-Boc-serine benzyl ester. In a round-bottomed flask were placed The mixture was partitioned between water and ethyl acetate (1:1, 1000 ml) and aqueous layer was re-extracted with ethyl acetate(2×200 mL) The combined organic layers were washed with water (2×500 mL), saturated sodium chloride dried over sodium sulfate The solvents were removed in vacuo the crude material purified on silica gel

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

Procedure: To a solution of the compound of Formula XII(a), (S)-2-tert-butoxycarbonylamino-3-hydroxy-propionic acid benzyl ester (1.7 g, 5.76 mmol) in dichloromethane (50 mL) was added trimethyloxonium tetrafluoroborate (1.11 g, 7.50 mmol), followed by the portion-wise addition of proton sponge (1.61 g, 7.50 mmol). After stirring for 24 hrs at RT, the solution was concentrated, and the residue was dissolved in ethyl acetate, and the solution filtered through a pad of celite. The filtrate was washed with 1 M HCl and brine. The organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Silica-gel flash chromatography with 5% to 15% ethyl acetate in hexanes afforded the compound of Formula XIII(b), (S)-2-tert-butoxycarbonylamino-3-methoxy-propionic acid benzyl ester (1.24 g, 69.6%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ (ppm) 7.35-7.29 (m, 5H), 4.90-4.87 (m, 1H), 4.51 (s, 2H), 3.92-3.87 (m, 1H), 3.80-3.78 (m, 1H), 3.56 (dd, 2H), 3.42 (dd, 1H), 3.33 (s, 3H), 1.42 (s, 9H). the solution was concentrated the residue was dissolved in ethyl acetate the solution filtered through a pad of celite The filtrate was washed with 1 M HCl and brine The organic layers were dried over MgSO4 filtered concentrated in vacuo

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

Procedure: To a solution of the compound of Formula XII(a), (S)-2-tert-butoxycarbonylamino-3-hydroxy-propionic acid benzyl ester (1.7 g, 5.76 mmol) in dichloromethane (50 mL) was added trimethyloxonium tetrafluoroborate (1.11 g, 7.50 mmol), followed by the portion-wise addition of proton sponge (1.61 g, 7.50 mmol). After stirring for 24 hrs at RT, the solution was concentrated, and the residue was dissolved in ethyl acetate, and the solution filtered through a pad of celite. The filtrate was washed with 1 M HCl and brine. The organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Silica-gel flash chromatography with 5% to 15% ethyl acetate in hexanes afforded the compound of Formula XIII(b), (S)-2-tert-butoxycarbonylamino-3-methoxy-propionic acid benzyl ester (1.24 g, 69.6%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ (ppm) 7.35-7.29 (m, 5H), 4.90-4.87 (m, 1H), 4.51 (s, 2H), 3.92-3.87 (m, 1H), 3.80-3.78 (m, 1H), 3.56 (dd, 2H), 3.42 (dd, 1H), 3.33 (s, 3H), 1.42 (s, 9H). the solution was concentrated the residue was dissolved in ethyl acetate the solution filtered through a pad of celite The filtrate was washed with 1 M HCl and brine The organic layers were dried over MgSO4 filtered concentrated in vacuo

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The N-Boc-serine benzyl ester was brought up in dichloromethane (170 mL) and treated with carbon tetrabromide (26.37 g, 79.51 mmol, 1.2 eq.), and triphenylphosphine (25.20 g, 96.08 mmol, 1.45 eq.) and the solution was stirred at 0° C. for 30 min. The volatiles were then evaporated in vacuo and the residue was triturated with ether (1000 mL). The solid that separated out was filtered off and organic layer was evaporated in vacuo to get the crude product. The crude material was purified by flash chromatography on silica gel to get N-Boc-β-bromoalanine benzyl ester. The volatiles were then evaporated in vacuo the residue was triturated with ether (1000 mL) The solid that separated out was filtered off organic layer was evaporated in vacuo to get the crude product The crude material was purified by flash chromatography on silica gel

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The N-Boc-serine benzyl ester was brought up in dichloromethane (170 mL) and treated with carbon tetrabromide (26.37 g, 79.51 mmol, 1.2 eq.), and triphenylphosphine (25.20 g, 96.08 mmol, 1.45 eq.) and the solution was stirred at 0° C. for 30 min. The volatiles were then evaporated in vacuo and the residue was triturated with ether (1000 mL). The solid that separated out was filtered off and organic layer was evaporated in vacuo to get the crude product. The crude material was purified by flash chromatography on silica gel to get N-Boc-β-bromoalanine benzyl ester. The volatiles were then evaporated in vacuo the residue was triturated with ether (1000 mL) The solid that separated out was filtered off organic layer was evaporated in vacuo to get the crude product The crude material was purified by flash chromatography on silica gel

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

Procedure: In a round-bottomed flask were placed N-BocSerine (20.0 g, 89.605 mmol, 1 eq.), benzyl bromide (10.76 ml, 90.50 mmol, 1.01 eq.) and cesium carbonate (56.64 g, 173.84 mmol, 1.94 eq.) in DMF (180 mL). The suspension was stirred under nitrogen at room temperature for 2 hrs to overnight. The mixture was partitioned between water and ethyl acetate (1:1, 1000 ml) and aqueous layer was re-extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with water (2×500 mL), saturated sodium chloride, and dried over sodium sulfate. The solvents were removed in vacuo and the crude material purified on silica gel to get N-Boc-serine benzyl ester. In a round-bottomed flask were placed The mixture was partitioned between water and ethyl acetate (1:1, 1000 ml) and aqueous layer was re-extracted with ethyl acetate (2×200 mL) The combined organic layers were washed with water (2×500 mL), saturated sodium chloride dried over sodium sulfate The solvents were removed in vacuo the crude material purified on silica gel

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

Procedure: In a round-bottomed flask were placed N-BocSerine (20.0 g, 89.605 mmol, 1 eq.), benzyl bromide (10.76 ml, 90.50 mmol, 1.01 eq.) and cesium carbonate (56.64 g, 173.84 mmol, 1.94 eq.) in DMF (180 mL). The suspension was stirred under nitrogen at room temperature for 2 hrs to overnight. The mixture was partitioned between water and ethyl acetate (1:1, 1000 ml) and aqueous layer was re-extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with water (2×500 mL), saturated sodium chloride, and dried over sodium sulfate. The solvents were removed in vacuo and the crude material purified on silica gel to get N-Boc-serine benzyl ester. In a round-bottomed flask were placed The mixture was partitioned between water and ethyl acetate (1:1, 1000 ml) and aqueous layer was re-extracted with ethyl acetate (2×200 mL) The combined organic layers were washed with water (2×500 mL), saturated sodium chloride dried over sodium sulfate The solvents were removed in vacuo the crude material purified on silica gel

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

Procedure: In an inert atmosphere and under exclusion of moisture, at 0° C. a solution of 6.9 g (102 mmol) of imidazol in 80 ml of dichloromethane was treated dropwise within 15 minutes with a solution of 2.2 ml (30 mmol) of thionylchloride in 30 ml of dichloromethane. After complete addition, the reaction mixture was left to warm to room temperature and stirring was continued for 30 minutes. Thereafter, a solution of 5.0 g (17 mmol) of (S)-2-tert-butoxycarbonylamino-3-hydroxy-propionic acid benzyl ester in 20 ml of dichloromethane was added dropwise at −78° C. After 1 hour at −78° C., the reaction mixture was left to warm to room temperature and stirring was continued overnight. For the working-up, the reaction mixture was quenched with 150 ml of a solution (10%) of citric acid. The organic layer was separated, washed with water, dried over sodium sulfate, and evaporated. The crude product (5.5 g of a colourless oil) was dissolved in 50 ml of ethyl acetate and cooled to 0° C. Thereafter, an aqueous solution (10%) of 9.0 g (29 mmol) of sodium metaperiodate, cooled to 0° C., and 0.36 g (2 mmol) of ruthenium(IV)oxide hydrate were added. After stirring at 0° C. for 30 minutes, the organic layer was separated, filtered over Dicalit and silica gel, and, finally, evaporated under reduced pressure. There were obtained 4.0 g (66%) of the (S)-2,2-dioxo-2λ6-[1,2,3]oxathiazolidine-3,4-dicarboxylic acid 4-benzyl ester 3-tert-butyl ester as a grey solid, [α]589=−21.51° (c=1.0% in MeOH), MS m/e (%): 356.0 (M−H+, 100). After complete addition the reaction mixture was left After 1 hour at −78° C. the reaction mixture was left to warm to room temperature stirring was continued overnight the reaction mixture was quenched with 150 ml of a solution (10%) of citric acid The organic layer was separated washed with water dried over sodium sulfate evaporated The crude product (5.5 g of a colourless oil) was dissolved in 50 ml of ethyl acetate cooled to 0° C After stirring at 0° C. for 30 minutes the organic layer was separated filtered over Dicalit and silica gel finally, evaporated under reduced pressure

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under an inert atmosphere, a solution of 6.5 g (25 mmol) of triphenylphosphine in 20 ml of tetrahydrofurane was treated with at 0° C. with 3.9 ml (25 mmol) of diethyl azodicarboxylate. Thereupon, 3.0 g (17 mmol) of 2-chloro-6-nitrophenol were added and the reaction mixture was stirred at 0° C. for 15 minutes. Finally, 4.93 g (17 mmol) of (S)-2-tert-butoxycarbonylamino-3-hydroxy-propionic acid benzyl ester were added and the reaction mixture was left to warm to room temperature. After stirring for 18 hours, for the working-up the solvent was evaporated under reduced pressure and the residue triturated in ether at 0° C. The precipitated triphenylphosphinoxide was filtered and washed with ether. The combined filtrates were evaporated to yield 12.8 g of the crude product as a brown-yellow oil. The crude product was purified by chromatography on silica gel using heptane and ethyl acetate as the eluent. There were obtained 3.9 g (50%) of the title compound as a yellow oil, [α]589=−5.96° (c=1.0% in MeOH), MS m/e (%): 468.1 (M+NH4+, 100). the reaction mixture was left to warm to room temperature After stirring for 18 hours was evaporated under reduced pressure the residue triturated in ether at 0° C The precipitated triphenylphosphinoxide was filtered washed with ether The combined filtrates were evaporated to yield 12.8 g of the crude product as a brown-yellow oil The crude product was purified by chromatography on silica gel

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The N-Boc-serine benzyl ester was brought up in dichloromethane (170 mL) and treated with carbon tetrabromide (26.37 g, 79.51 mmol, 1.2 eq.), and triphenylphosphine (25.20 g, 96.08 mmol, 1.45 eq.) and the solution was stirred at 0° C. for 30 min. The volatiles were then evaporated in vacuo and the residue was triturated with ether (1000 mL). The solid that separated out was filtered off and organic layer was evaporated in vacuo to get the crude product. The crude material was purified by flash chromatography on silica gel to get N-Boc-β-bromoalanine benzyl ester. The volatiles were then evaporated in vacuo the residue was triturated with ether (1000 mL) The solid that separated out was filtered off organic layer was evaporated in vacuo to get the crude product The crude material was purified by flash chromatography on silica gel