tert-butyl (2S,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate

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

Procedure: To a stirred solution of trans-1-tert-butoxycarbonyl-(2S)-hydroxymethyl-4-hydroxypyrrolidine (2.17 g, 10.0 mmol) and imidazole (2.04 g, 30.0 mmol) in DMF (50 ml) was added TBDPS-Cl (3.03 g, 11.0 mmol) at 0° C. The reaction mixture was stirred at room temperature for 18 hr. Water was added thereto, and extracted with EtOAc. The extract was washed with water, then dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc(3:2, v/v) as eluent to give trans-1-tert-butoxycarbonyl-(2S)-(tert-butyldiphenylsilyloxy)methyl-4-hydroxypyrrolidine (1.5 g, 33%) as a white crystalline solid. 1H-NMR (CDCl3) δ 1.03 (s9H), 1.25 and 1.32 (each s, 9H), 1.90–2.10 (m, 1H), 2.30–2.40 (m, 1H), 3.40–3.80 (m, 3H), 3.95–4.15 (m, 2H), 4.45–4.55 (m, 1H), 7.37–7.39 (m, 6H), 7.63–7.64 (m, 4H). extracted with EtOAc The extract was washed with water dried over Na2SO4 concentrated in vacuo The residue was purified by column chromatography on silica gel with n-hexane-EtOAc(3:2

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

Procedure: tert-Butyl (2S,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (500 mg; 2.3 mmol) in pyridine (20 mL) was cooled to 0° C. To this cooled solution was added a solution of p-toluenesulfonyl chloride (483 mg, 2.53 mmol) in pyridine (5 mL) over a period of 1 hour. The reaction mixture was allowed to slowly warm to ambient temperature and stirring was continued at ambient for 48 hours. The volatiles were removed in vacuo, and the residue was redissolved in toluene and concentrated again in vacuo. The crude material was triturated with ethyl acetate. This was further purified by chromatography on a 12 g silica gel column eluted with 5% ethyl acetate/hexanes for 3 minutes and then eluted with a gradient to 100% ethyl acetate over 20 minutes. The title compound was isolated as an oil (397 mg; 64% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.82-7.69 (m, 2H), 7.48 (d, J=7.9 Hz, 2H), 4.92 (d, J=2.8 Hz, 1H), 4.23-3.82 (m, 4H), 3.12 (dd, J=25.5, 13.9 Hz, 2H), 2.42 (d, J=3.6 Hz, 3H), 1.87 (d, J=20.3 Hz, 2H), 1.35 (dd, J=23.0, 13.0 Hz, 9H). The volatiles were removed in vacuo the residue was redissolved in toluene concentrated again in vacuo The crude material was triturated with ethyl acetate This was further purified by chromatography on a 12 g silica gel column eluted with 5% ethyl acetate/hexanes for 3 minutes eluted with a gradient to 100% ethyl acetate over 20 minutes

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

Procedure: tert-Butyl (2S,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (500 mg; 2.3 mmol) in pyridine (20 mL) was cooled to 0° C. To this cooled solution was added a solution of p-toluenesulfonyl chloride (483 mg, 2.53 mmol) in pyridine (5 mL) over a period of 1 hour. The reaction mixture was allowed to slowly warm to ambient temperature and stirring was continued at ambient for 48 hours. The volatiles were removed in vacuo, and the residue was redissolved in toluene and concentrated again in vacuo. The crude material was triturated with ethyl acetate. This was further purified by chromatography on a 12 g silica gel column eluted with 5% ethyl acetate/hexanes for 3 minutes and then eluted with a gradient to 100% ethyl acetate over 20 minutes. The title compound was isolated as an oil (397 mg; 64% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.82-7.69 (m, 2H), 7.48 (d, J=7.9 Hz, 2H), 4.92 (d, J=2.8 Hz, 1H), 4.23-3.82 (m, 4H), 3.12 (dd, J=25.5, 13.9 Hz, 2H), 2.42 (d, J=3.6 Hz, 3H), 1.87 (d, J=20.3 Hz, 2H), 1.35 (dd, J=23.0, 13.0 Hz, 9H). The volatiles were removed in vacuo the residue was redissolved in toluene concentrated again in vacuo The crude material was triturated with ethyl acetate This was further purified by chromatography on a 12 g silica gel column eluted with 5% ethyl acetate/hexanes for 3 minutes eluted with a gradient to 100% ethyl acetate over 20 minutes

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

Procedure: To a solution of compound 236 (6.4 g, 26.09 mmol) in THF (80 mL) at 0° C. was added a solution of LiBH4 (2.063 g, 94.76 mmol) in one shot. The suspension was stirred at 0° C. for 1 h then at room temperature overnight. The mixture was cooled to 0° C. and water (52 mL) then 6N HCl (20 mL) were added. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×70 mL). The combined organics were washed with 2N NaOH, 2N HCl and brine (20 mL each). The organic layers were dried over Na2SO4 filtered and concentrated to afford title compound 237 (5.4 g, 95%) as clear oil. LRMS (ESI): (calc.) 217.13. (found) 256.3 (M+K). at room temperature overnight The mixture was cooled to 0° C. The layers were separated the aqueous layer was extracted with ethyl acetate (3×70 mL) The combined organics were washed with 2N NaOH, 2N HCl and brine (20 mL each) The organic layers were dried over Na2SO4 filtered concentrated

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

Procedure: To a solution of compound 236 (6.4 g, 26.09 mmol) in THF (80 mL) at 0° C. was added a solution of LiBH4 (2.063 g, 94.76 mmol) in one shot. The suspension was stirred at 0° C. for 1 h then at room temperature overnight. The mixture was cooled to 0° C. and water (52 mL) then 6N HCl (20 mL) were added. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×70 mL). The combined organics were washed with 2N NaOH, 2N HCl and brine (20 mL each). The organic layers were dried over Na2SO4 filtered and concentrated to afford title compound 237 (5.4 g, 95%) as clear oil. LRMS (ESI): (calc.) 217.13. (found) 256.3 (M+K). at room temperature overnight The mixture was cooled to 0° C. The layers were separated the aqueous layer was extracted with ethyl acetate (3×70 mL) The combined organics were washed with 2N NaOH, 2N HCl and brine (20 mL each) The organic layers were dried over Na2SO4 filtered concentrated

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

Procedure: (2S,4R)-tert-butyl 4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (5.40 g, 25.84 mmol) and 4-methylbenzene-1-sulfonyl chloride (14.22 g, 74.6 mmol) were combined in pyridine (50 mL) at 0° C. and store in the refrigerator for 3 days. The reaction mixture was concentrated to half the volume under vacuo and some water (˜300 mL) was added slowly. The mixture was stirred 1 h until a white solid formed. The solid was filtered and dried on the pump on high-vacuum over night. The solid was recrystallized from MeOH (˜20 ml) and water (few drops) to afford title compound 204 (6.40 g, 49%). LRMS: (calc) 525.15. (found) 426.4 (MH-Boc)+. The reaction mixture was concentrated to half the volume under vacuo some water (˜300 mL) was added slowly formed The solid was filtered dried on the pump on high-vacuum over night The solid was recrystallized from MeOH (˜20 ml) and water (few drops)

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

Procedure: To a 0° C. solution of (2S,4R)-tert-butyl 4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.0 equiv) and Et3N (1.05 equiv) in dichloromethane (0.5 M) was added TBSCl (1.05 equiv), followed by a few crystals of DMAP. The solution was allowed to warm to room temperature and stirred overnight. The reaction mixture was then diluted with dichloromethane, and washed with sat'd. aq. NaHCO3. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the title compound (95%), which was used without further purification. washed with sat'd The organic layer was dried over anhydrous sodium sulfate filtered concentrated in vacuo

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

Procedure: To a 0° C. solution of (2S,4R)-tert-butyl 4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.0 equiv) and Et3N (1.05 equiv) in dichloromethane (0.5 M) was added TBSCl (1.05 equiv), followed by a few crystals of DMAP. The solution was allowed to warm to room temperature and stirred overnight. The reaction mixture was then diluted with dichloromethane, and washed with sat'd. aq. NaHCO3. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the title compound (95%), which was used without further purification. washed with sat'd The organic layer was dried over anhydrous sodium sulfate filtered concentrated in vacuo

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

Procedure: To a 0° C. suspension of LiBH4 (2.0 equiv) in THF (0.67 M) was slowly added TMSCl (4.0 equiv) by syringe. After stirring at room temperature for 30 minutes, (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (1.0 equiv) was then added, and the resulting mixture was stirred at room temperature overnight. The reaction was quenched by the careful addition of sat'd. aq. NaHCO3, and the mixture was diluted with EtOAc, and the organice layer was washed twice with sat'd. aq. NaHCO3, once with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The title compound was isolated in 65% yield and used without further purification. the resulting mixture was stirred at room temperature overnight The reaction was quenched by the careful addition of sat'd aq. NaHCO3, and the mixture was diluted with EtOAc the organice layer was washed twice with sat'd aq. NaHCO3, once with brine, dried over anhydrous sodium sulfate filtered concentrated in vacuo

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

Procedure: 1-N-Boc-(2S,4R)-4-hydroxy-2-(hydroxymethyl)-pyrrolidine (500 mg) was dissolved in DMF (4.0 ml), and imidazole (164 mg) was added to the dissolution. After cooling to 0° C., tert-butylchlorodiphenylsilane (616 μl) was added to the mixture, and stirred for 1 hour. Ethyl acetate and a saturated aqueous sodium bicarbonate solution were added to the reaction mixture to separate the organic layer. After being washed with a saturated sodium chloride solution, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a colorless, oily substance (655 mg). Physical properties: m/z [M+H]+ 456.2 to separate the organic layer After being washed with a saturated sodium chloride solution the organic layer was dried over anhydrous sodium sulfate the solvent was distilled off under reduced pressure The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate)

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

Procedure: 1-N-Boc-(2S,4R)-4-hydroxy-2-(hydroxymethyl)-pyrrolidine (500 mg) was dissolved in DMF (4.0 ml), and imidazole (164 mg) was added to the dissolution. After cooling to 0° C., tert-butylchlorodiphenylsilane (616 μl) was added to the mixture, and stirred for 1 hour. Ethyl acetate and a saturated aqueous sodium bicarbonate solution were added to the reaction mixture to separate the organic layer. After being washed with a saturated sodium chloride solution, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a colorless, oily substance (655 mg). Physical properties: m/z [M+H]+ 456.2 to separate the organic layer After being washed with a saturated sodium chloride solution the organic layer was dried over anhydrous sodium sulfate the solvent was distilled off under reduced pressure The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate)

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

Procedure: To a 0° C. solution of (2S,4R)-tert-butyl 4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.0 equiv) and Et3N (1.05 equiv) in dichloromethane (0.5 M) was added TBSCl (1.05 equiv), followed by a few crystals of DMAP. The solution was allowed to warm to room temperature and stirred overnight. The reaction mixture was then diluted with dichloromethane, and washed with sat'd. aq. NaHCO3. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the title compound (95%), which was used without further purification. washed with sat'd The organic layer was dried over anhydrous sodium sulfate filtered concentrated in vacuo