tert-butyl (3S,4S)-3-azido-4-hydroxypyrrolidine-1-carboxylate

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

実験手順: (3S,4S)-3-(4-Phenoxybenzenesulfonamido)-4-mercaptopyrrolidine Hydrochloride. A solution of (3S,4S)—N-Boc-3-azido-4-hydroxypyrrolidine (850 mg, 3.72 mmol) and triethylamine (622 μL, 4.46 mmol) in CH2Cl2 (10 mL) was cooled with stirring to 0° C., and methanesulfonyl chloride (331 μl, 4.28 mmol) was added dropwise. The solution was stirred at room temperature until no starting material was detected by TLC (25% ethyl acetate in hexane). The reaction mixture was washed with 10% aq. citric acid, water, dried over Na2SO4 and evaporated. The residual crude methanesulfonate was dissolved in anhydrous DMF (20 mL), potassium acetate (1.10 g, 11.2 mmol) was added, and the mixture was stirred at 105° C. under nitrogen for 6 hr. The reaction mixture was poured into ice water and was extracted with ethyl acetate (20 ml×3). The organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (25% ethyl acetate in hexane) to give (3S,4R)—N-Boc-3-azido-4-acetoxypyrrolidine (860 mg, 86%): 1H NMR (300 MHz, CDCl3) δ 5.31 (br m, 1H), 4.07 (m, 1H), 3.60-3.71 (m, 2H), 3.36-3.50 (m, 2H), 2.16 (s, 3H), 1.46 (s, 9H); [α]20D=−34.5° (c=1.00, CHCl3). The solution was stirred at room temperature until no starting material The reaction mixture was washed with 10% aq. citric acid, water dried over Na2SO4 evaporated The residual crude methanesulfonate was dissolved in anhydrous DMF (20 mL) the mixture was stirred at 105° C. under nitrogen for 6 hr was extracted with ethyl acetate (20 ml×3) The organic layer was washed with brine dried over Na2SO4 evaporated The residue was purified by flash chromatography (25% ethyl acetate in hexane)

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

実験手順: A sample of the (3S,4S)—N-Boc-3-azido-4-hydroxypyrrolidine (80 mg, 0.35 mmol) was dissolved in trifluoroacetic acid (1 mL) and was stirred until no starting material was detected on TLC (25% ethyl acetate in hexane). The solution was evaporated under reduce pressure and the residue was dissolved in CH2Cl2 (2 mL). The solution was cooled to 0° C., triethylamine (117 μL, 0.84 mmol) and Cbz-Cl (60 mg, 0.35 mmol) were added, and the resulting solution was stirred for 2 hr at room temperature. The reaction mixture was washed with water, dried over Na2SO4, and evaporated. The residue was purified by flash chromatography (25% ethyl acetate in hexane) to give (3S,4S)—N-Cbz-3-azido-4-hydroxypyrrolidine (89 mg, 97%): [α]20D=+ 16.1° (c=1.00, CHCl3). Lit. [Kamal, A.; Shaik, A. A.; Sandbhor, M.; Malik, M. S.; Kaga, H. Tetrahedron Lett. 2004, 45, 8057-8059] for (3S,4S)—N-Cbz-3-azido-4-hydroxypyrrolidine: [0]25D=+14.3° (c=1.06, CHCl3). The solution was evaporated the residue was dissolved in CH2Cl2 (2 mL) the resulting solution was stirred for 2 hr at room temperature The reaction mixture was washed with water dried over Na2SO4 evaporated The residue was purified by flash chromatography (25% ethyl acetate in hexane)

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

実験手順: 96.1 A suspension of 210 mg NaH (55% in mineral oil) in 3 ml DMF was treated at 0° C. with 1.0 g (3S,4S)-3-azido-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester in 6 ml DMF. The reaction mixture was stirred at 0° C. for 90 min, then it was cooled to 0° C. A solution of 0.53 ml ethyl bromoacetate was added dropwise. The reaction mixture was slowly warmed to r.t., stirred overnight, then heated for 1 hr at 50° C. After cooling to r.t. the mixture was taken up in EtOAc and washed with H2O. The combined organics were dried over MgSO4, filtrated and concentrated. The crude product was purified by column chromatography (silica gel; cyclohexane->cyclohexane/EtOAc 3:2) to give 584 mg (3S,4S)-3-azido-4-ethoxycarbonylmethoxy-pyrrolidine-1-carboxylic acid tert-butyl ester as yellow liquid. MS 315.2 ([M+H]+) it was cooled to 0° C The reaction mixture was slowly warmed to r.t. stirred overnight heated for 1 hr at 50° C After cooling to r.t. the mixture washed with H2O The combined organics were dried over MgSO4 filtrated concentrated The crude product was purified by column chromatography (silica gel; cyclohexane->cyclohexane/EtOAc 3:2)

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

実験手順: 38.1 A solution of 530 mg (3S,4S)-3-azido-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (example 22.2) in 5 ml pyridine was cooled to 0° C. under an argon atmosphere and treated with 664 mg 4-toluenesulfonyl chloride. The mixture was slowly warmed to room temperature and stirred for 6 hrs. The pyridine was distilled off. The residue was taken up in CH2Cl2 and 10% aq. Na2CO3. The organic phase was washed with H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel, gradient: cyclohexane->cyclohexane/EtOAc 7:3) to give 628 mg (3S,4S)-3-azido-4-(toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester as viscous yellow oil. MS 405.3 ([M+Na]+) The pyridine was distilled off The organic phase was washed with H2O and brine dried over MgSO4 filtered concentrated The crude product was purified by column chromatography (silica gel, gradient: cyclohexane->cyclohexane/EtOAc 7:3)

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

実験手順: 37.1 To stirred, cooled (−78° C.) solution of 695 mg (3S,4S)-3-azido-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (example 22.2) in 5 ml CH2Cl2 under an argon atmosphere were added 2.69 g bis(2-methoxyethyl)aminosulphur trifluoride (50% solution in THF). The dry ice bath was removed and the mixture was allowed to warm to r.t. and stirring was continued for 22 h. The mixture was poured into 10% aq. Na2CO3. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated. The crude product was purified by chromatography (silica gel; gradient: cyclohexane->cyclohexane/EtOAc 3:2) to give 424 mg (S)-3-azido-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester as light yellow oil. MS 409.0 ([M+H]+) The dry ice bath was removed stirring The mixture was poured into 10% aq. Na2CO3 The organic phase was washed with brine dried (MgSO4) filtered concentrated The crude product was purified by chromatography (silica gel; gradient: cyclohexane->cyclohexane/EtOAc 3:2)

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

実験手順: 24.1 A solution of 1.0 g (3S,4S)-3-azido-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (example 22.2) in 15 ml acetonitrile and 3 ml THF was treated with 3.0 g silver(I) oxide and and 2.7 ml iodomethane. The reaction mixture was stirred over night at r.t., then again treated with 3.0 g silver(I) oxide and 2.7 ml iodomethane. The reaction was agitated over night at r.t., then filtrated. The filtrate was concentrated. The crude product was purified by chromatography (silica gel; cyclohexane/EtOAc 2:1) to give 1.0 g (3S,4S)-3-azido-4-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester as light yellow oil. MS 243.4 ([M+H]+) The reaction was agitated over night at r.t. filtrated The filtrate was concentrated The crude product was purified by chromatography (silica gel; cyclohexane/EtOAc 2:1)

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

実験手順: 22.3 A solution of 2.0 g (3S,4S)-3-azido-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester in 25 MeOH was treated under an argon atmosphere with 100 mg PtO2. The reaction mixture was stirred over night under a hydrogen atmosphere. The catalyst was filtered off and washed with methanol. The filtrate was concentrated. The crude product was purified by chromatography (silica gel; gradient: CH2Cl2->CH2Cl2/MeOH 4:1) to give 1.5 g (3S,4S)-3-amino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester as off-white solid. MS 202.9 ([M+H]+) The catalyst was filtered off washed with methanol The filtrate was concentrated The crude product was purified by chromatography (silica gel; gradient: CH2Cl2->CH2Cl2/MeOH 4:1)