tert-butyl N-[(2S)-1-hydroxy-3-phenylpropan-2-yl]carbamate

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Oxalyl chloride in anhydrous CH2Cl2 (2.0M, 6.0 mL, 12.0 mmol) was treated with dimethylsulfoxide (1.0 mL, 14.1 mmol) in anhydrous CH2Cl2 (3 mL) dropwise over 5 minutes at −78° C. under a dry N2 atmosphere. The mixture was stirred at −78° C. for 15 minutes and then treated with (2S)-2-(tert-butoxycarbonylamino)-3-phenyl-1-propanol (2.0 g, 8.0 mmol) in anhydrous CH2Cl2 (6 mL) dropwise over 10 minutes. The mixture was stirred at −78° C. for 30 minutes and then treated with triethylamine (4.4 mL, 31.7 mmol) in anhydrous CH2Cl2 (6 mL) dropwise over 10 minutes. The mixture was allowed to slowly warm to ambient temperature, stirred for 1 hour, diluted with CH2Cl2 (100 mL), washed with 10% aqueous citric acid (50 mL), water (50 mL), saturated NaHCO3 (50 mL), dried over Na2SO4, filtered, and the solvent removed under reduced pressure to provide the title compound as an off-white crystalline solid (2.0 g). The mixture was stirred at −78° C. for 30 minutes to slowly warm to ambient temperature stirred for 1 hour washed with 10% aqueous citric acid (50 mL), water (50 mL), saturated NaHCO3 (50 mL) dried over Na2SO4 filtered the solvent removed under reduced pressure

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (2S)-2-(tert-Butoxycarbonylamino)-3-phenyl-1-propanol (2.0 g, 8.0 mmol) in anhydrous THF (50 mL) at 0° C. under a dry N2 atmosphere was treated with triphenylphosphine (2.5 g, 9.5 mmol) and diethyl azodicarboxylate (1.66 g, 9.5 mmol). The mixture was stirred at 0° C. for 1 hour, allowed to warm to ambient temperature and stirred overnight. The mixture was partitioned between water (50 mL) and ethyl acetate (2×50 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexanes:CH2Cl2, 1:1) to provide the title compound as a colorless oil (1.4 g, 76%). Rf=0.54 (hexanes:ethyl acetate, 2:1); 1H NMR (CDCl3) δ 7.32-7.19 (m, 5H), 3.01-2.90 (m, 1H), 2.70-2.56 (m, 2H), 2.30 (m, 1H), 2.03 (m, 1H), 1.44 (s, 9H). to warm to ambient temperature stirred overnight The mixture was partitioned between water (50 mL) and ethyl acetate (2×50 mL) dried over Na2SO4 filtered concentrated under reduced pressure The residue was purified by column chromatography on silica gel (hexanes:CH2Cl2, 1:1)

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To dimethyl sulfoxide (2.82 mL, 39.8 mmol) dissolved in anhydrous methylene chloride (5 mL) and cooled to -78° C. was added dropwise oxalyl chloride (2.6 mL, 1.5 equiv). After 10 minutes at -78° C., N-Boc-Phenylalaninol (5.00 g, 19.9 mmol) dissolved in anhydrous methylene chloride (75 mL) was cannulated into the reaction mixture. After 15 minutes at -78° C., the reaction was stirred for 2 minutes at 0° C. and then cooled again to -78° C. Triethylamine (11.9 mL, 4.3 equiv) was added dropwise. After 25 minutes, the reaction was quenched with cooled 10% citric acid (15 mL) and then diluted with additional 10% citric acid (75 mL). Ether (300 mL) was added and the solution was washed with water (5×100 mL), brine, water (5×100 mL), and brine, dried over sodium sulfate, and concentrated under reduced pressure to afford the title compound (4.22 g). After 15 minutes at -78° C. cooled again to -78° C After 25 minutes the reaction was quenched with cooled 10% citric acid (15 mL) diluted with additional 10% citric acid (75 mL) Ether (300 mL) was added the solution was washed with water (5×100 mL), brine, water (5×100 mL), and brine dried over sodium sulfate concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution containing N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine, methyl ester (10 g, 35.8 mmole) dissolved in a mixture of tetrahydrofuran (190 ml) and absolute ethanol (190 ml) is added lithium chloride (6.09 g, 143.2 mmole). The resulting homogeneous solution is treated with sodium borohydride (5.42 g, 143.2 mmole) and the reaction is stirred at room temperature under argon for 24 hours. The reaction mixture is next filtered using ether (~700 ml) to rinse the filter cake. The resulting filtrate is rinsed with water (3×200 ml) and brine (200 ml), dried over magnesium sulfate, and concentrated in vacuo to give 9 g of crude product. Recrystallization from ether/hexane gives 7.59 g of the title D compound,; m.p. 94°-96°. The reaction mixture is next filtered to rinse the filter cake The resulting filtrate is rinsed with water (3×200 ml) and brine (200 ml) dried over magnesium sulfate concentrated in vacuo

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The recovered intermediate (20a) (8.5 g, 33 mmol, 1.0 eq) was dissolved into 70 mL pyridine containing potassium hydroxide (2.1 g, 37 mmol, 1.1 eq) and the mixture was chilled in an ice bath. Tosyl chloride (7.1 g, 37 mmol, 1.1 eq) was added and the mixture was stirred at 0° C. for 2 hours then refrigerated overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure. The recovered residue was dissolved into 300 mL EtOAc, washed with 2×200 mL 1M H3PO4, saturated bicarbonate, and saturated aqueous NaCl. The organic was dried over MgSO4 and concentrated under reduced pressure to yield intermediate (20b) (10.3 g) as a pale brown oil. the mixture was chilled in an ice bath then refrigerated overnight The mixture was filtered the filtrate was concentrated under reduced pressure The recovered residue was dissolved into 300 mL EtOAc washed with 2×200 mL 1M H3PO4, saturated bicarbonate, and saturated aqueous NaCl The organic was dried over MgSO4 concentrated under reduced pressure

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a 0° C. solution of (S)-tert-butyl (1-hydroxy-3-phenylpropan-2-yl)carbamate (Alfa Aesar, 500 mg, 1.99 mmol) in DMF (13.0 mL) was added NaH (60% in mineral oil, 119 mg, 2.98 mmol). The resulting reaction mixture was stirred at 0° C. for 15 min and then (2-bromoethoxy)(tert-butyl)dimethylsilane (512 μL, 2.39 mmol) was added. The reaction mixture was stirred at 0° C. for 2 h and then at room temperature for 3 h. The mixture was poured into a separatory funnel containing EtOAc and sat. aq. NH4Cl. The aqueous layer was extracted with EtOAc (3×), and the combined organics were washed with sat. NaCl, dried over Na2SO4, filtered and concentrated in vacuo. The crude oil was purified using flash chromatography (40 g column, gradient from 0% to 40% EtOAc/hexanes over 14 min) to give the title compound (124 mg, 15%) as a colorless oil. MS (ESI+) m/z 310.1 (M+H−Boc)+. The resulting reaction mixture The reaction mixture was stirred at 0° C. for 2 h at room temperature for 3 h The mixture was poured into a separatory funnel The aqueous layer was extracted with EtOAc (3×) the combined organics were washed with sat. NaCl dried over Na2SO4 filtered concentrated in vacuo The crude oil was purified flash chromatography (40 g column, gradient from 0% to 40% EtOAc/hexanes over 14 min)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To 5.7 g (0.023 mol) of Boc-PheOH dissolved in THF (30 mL) at −10° C. under N2 are added NMM (2.5 mL, 0.023 mol) and IBCF (3 mL, 0.023 mol). The reaction mixture is stirred for 15 minutes and filtered. The filtrate is slowly added to an ice-cold solution of NaBH4 (2.3 g, 0.061 mol) in H2O (10 mL) and then stirred for 1 hour at ice-bath temperature followed by stirring for 1 hour at room temperature. The reaction is cooled to 0° C., treated with saturated NaHCO3 solution, extracted with EtOAc, washed with 1M HCl, washed with water, dried over anhydrous MgSO4, and evaporated to dryness. The crude product is purified over a silica gel column eluted with 95:5 EtOAc/MeOH. filtered stirred for 1 hour at ice-bath temperature by stirring for 1 hour at room temperature extracted with EtOAc washed with 1M HCl washed with water dried over anhydrous MgSO4 evaporated to dryness The crude product is purified over a silica gel column eluted with 95:5 EtOAc/MeOH

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To 5.7 g (0.023 mol) of Boc-PheOH dissolved in THF (30 mL) at −10° C. under N2 are added NMM (2.5 mL, 0.023 mol) and IBCF (3 mL, 0.023 mol). The reaction mixture is stirred for 15 minutes and filtered. The filtrate is slowly added to an ice-cold solution of NaBH4 (2.3 g, 0.061 mol) in H2O (10 mL) and then stirred for 1 hour at ice-bath temperature followed by stirring for 1 hour at room temperature. The reaction is cooled to 0° C., treated with saturated NaHCO3 solution, extracted with EtOAc, washed with 1M HCl, washed with water, dried over anhydrous MgSO4, and evaporated to dryness. The crude product is purified over a silica gel column eluted with 95:5 EtOAc/MeOH. filtered stirred for 1 hour at ice-bath temperature by stirring for 1 hour at room temperature extracted with EtOAc washed with 1M HCl washed with water dried over anhydrous MgSO4 evaporated to dryness The crude product is purified over a silica gel column eluted with 95:5 EtOAc/MeOH

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To dimethyl sulfoxide (2.82 mL, 39.8 mmol) dissolved in anhydrous methylene chloride (5 mL) and cooled to -78° C. was added dropwise oxalyl chloride (2.6 mL, 1.5 equiv). After 10 minutes at -78° C., N-Boc-Phenylalaninol (5.00 g, 19.9 mmol) dissolved in anhydrous methylene chloride (75 mL) was cannulated into the reaction mixture. After 15 minutes at -78° C., the reaction was stirred for 2 minutes at 0° C. and then cooled again to -78° C. Triethylamine (11.9 mL, 4.3 equiv) was added dropwise. After 25 minutes, the reaction was quenched with cooled 10% citric acid (15 mL) and then diluted with additional 10% citric acid (75 mL). Ether (300 mL) was added and the solution was washed with water (5×100 mL), brine, water (5×100 mL), and brine, dried over sodium sulfate, and concentrated under reduced pressure to afford the title compound (4.22 g). After 15 minutes at -78° C. cooled again to -78° C After 25 minutes the reaction was quenched with cooled 10% citric acid (15 mL) diluted with additional 10% citric acid (75 mL) Ether (300 mL) was added the solution was washed with water (5×100 mL), brine, water (5×100 mL), and brine dried over sodium sulfate concentrated under reduced pressure

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To dimethyl sulfoxide (2.82 mL, 39.8 mmol) dissolved in anhydrous methylene chloride (5 mL) and cooled to -78° C. was added dropwise oxalyl chloride (2.6 mL, 1.5 equiv). After 10 minutes at -78° C., N-Boc-Phenylalaninol (5.00 g, 19.9 mmol) dissolved in anhydrous methylene chloride (75 mL) was cannulated into the reaction mixture. After 15 minutes at -78° C., the reaction was stirred for 2 minutes at 0° C. and then cooled again to -78° C. Triethylamine (11.9 mL, 4.3 equiv) was added dropwise. After 25 minutes, the reaction was quenched with cooled 10% citric acid (15 mL) and then diluted with additional 10% citric acid (75 mL). Ether (300 mL) was added and the solution was washed with water (5×100 mL), brine, water (5×100 mL), and brine, dried over sodium sulfate, and concentrated under reduced pressure to afford the title compound (4.22 g). After 15 minutes at -78° C. cooled again to -78° C After 25 minutes the reaction was quenched with cooled 10% citric acid (15 mL) diluted with additional 10% citric acid (75 mL) Ether (300 mL) was added the solution was washed with water (5×100 mL), brine, water (5×100 mL), and brine dried over sodium sulfate concentrated under reduced pressure

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To dimethyl sulfoxide (2.82 mL, 39.8 mmol) dissolved in anhydrous methylene chloride (5 mL) and cooled to -78° C. was added dropwise oxalyl chloride (2.6 mL, 1.5 equiv). After 10 minutes at -78° C., N-Boc-Phenylalaninol (5.00 g, 19.9 mmol) dissolved in anhydrous methylene chloride (75 mL) was cannulated into the reaction mixture. After 15 minutes at -78° C., the reaction was stirred for 2 minutes at 0° C. and then cooled again to -78° C. Triethylamine (11.9 mL, 4.3 equiv) was added dropwise. After 25 minutes, the reaction was quenched with cooled 10% citric acid (15 mL) and then diluted with additional 10% citric acid (75 mL). Ether (300 mL) was added and the solution was washed with water (5×100 mL), brine, water (5×100 mL), and brine, dried over sodium sulfate, and concentrated under reduced pressure to afford the title compound (4.22 g). After 15 minutes at -78° C. cooled again to -78° C After 25 minutes the reaction was quenched with cooled 10% citric acid (15 mL) diluted with additional 10% citric acid (75 mL) Ether (300 mL) was added the solution was washed with water (5×100 mL), brine, water (5×100 mL), and brine dried over sodium sulfate concentrated under reduced pressure

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Oxalyl chloride in anhydrous CH2Cl2 (2.0M, 6.0 mL, 12.0 mmol) was treated with dimethylsulfoxide (1.0 mL, 14.1 mmol) in anhydrous CH2Cl2 (3 mL) dropwise over 5 minutes at −78° C. under a dry N2 atmosphere. The mixture was stirred at −78° C. for 15 minutes and then treated with (2S)-2-(tert-butoxycarbonylamino)-3-phenyl-1-propanol (2.0 g, 8.0 mmol) in anhydrous CH2Cl2 (6 mL) dropwise over 10 minutes. The mixture was stirred at −78° C. for 30 minutes and then treated with triethylamine (4.4 mL, 31.7 mmol) in anhydrous CH2Cl2 (6 mL) dropwise over 10 minutes. The mixture was allowed to slowly warm to ambient temperature, stirred for 1 hour, diluted with CH2Cl2 (100 mL), washed with 10% aqueous citric acid (50 mL), water (50 mL), saturated NaHCO3 (50 mL), dried over Na2SO4, filtered, and the solvent removed under reduced pressure to provide the title compound as an off-white crystalline solid (2.0 g). The mixture was stirred at −78° C. for 30 minutes to slowly warm to ambient temperature stirred for 1 hour washed with 10% aqueous citric acid (50 mL), water (50 mL), saturated NaHCO3 (50 mL) dried over Na2SO4 filtered the solvent removed under reduced pressure