tert-butyl (2R,3S)-3-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate

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

Procedure: To a 0° C. solution of (2R,3S)-tert-butyl 3-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 (99%), 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 (0.5 M) was slowly added TMSCl (4.0 equiv) by syringe. After stirring at room temperature for 30 minutes, (2S,3S)-1-(tert-butoxycarbonyl)-3-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 organic 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 55% 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 organic layer was washed twice with sat'd aq. NaHCO3, once with brine, 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 (0.5 M) was slowly added TMSCl (4.0 equiv) by syringe. After stirring at room temperature for 30 minutes, (2S,3S)-1-(tert-butoxycarbonyl)-3-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 organic 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 55% 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 organic layer was washed twice with sat'd aq. NaHCO3, once with brine, 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 (2R,3S)-tert-butyl 3-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 (99%), 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 (0.5 M) was slowly added TMSCl (4.0 equiv) by syringe. After stirring at room temperature for 30 minutes, (2S,3S)-1-(tert-butoxycarbonyl)-3-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 55% 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:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 0° C. solution of (2R,3S)-tert-butyl 3-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 (99%), 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:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of (2R,3S)-tert-butyl 3-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (5.04 g, 23.20 mmol) and dibutyloxostannane (7.07 g, 27.84 mmol) in toluene (50 mL) is refluxed in a 130° C. oil bath for 2 h. The mixture is cooled to 0° C. in an ice bath for 30 min and treated with methanesulfonyl chloride (2.15 mL, 27.84 mmol) at once. The reaction is stirred for 30 min at 0° C. and then the mixture allowed to gradually warm to ambient temperature overnight. The solution is concentrated and the resulting residue purified by medium pressure liquid chromatography, eluting with ethyl acetate:hexane (8:2). Fractions containing pure product are combined and concentrated to give 6.14 g (96%) of dense oil as the title compound. LC-ES/MS m/z 318.2 [M+Na]+, TR=2.34 min. The mixture is cooled to 0° C. in an ice bath for 30 min to gradually warm to ambient temperature overnight The solution is concentrated the resulting residue purified by medium pressure liquid chromatography eluting with ethyl acetate:hexane (8:2) Fractions containing pure product concentrated

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

Procedure: A solution of 3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (13.29 g, 57.47 mmol) in tetrahydrofuran (130 mL) is treated with borane-methyl sulfide complex (16.06 mL, 172.41 mmol) dropwise and stirred overnight at room temperature. The mixture is cooled to 5° C. in a water ice bath and treated with 3 N aqueous hydrogen chloride solution (5 mL) dropwise until evolution of gas has ceased. The resulting suspension is stirred further for 30 min and diluted with 5 N aqueous sodium hydroxide solution until a white solid is dissolved. This is extracted with ethyl acetate (3×100 mL). The organic layer is washed with water (2×100 mL) and brine, dried over sodium sulfate, filtered, and concentrated to dryness. The resulting oil is dried under vacuum to give 10.03 g (80%) of the title compound. LC-ES/MS m/z 457.2 [2M+Na]+, TR=1.59 min. The mixture is cooled to 5° C. in a water ice bath The resulting suspension is stirred further for 30 min is dissolved This is extracted with ethyl acetate (3×100 mL) The organic layer is washed with water (2×100 mL) and brine dried over sodium sulfate filtered concentrated to dryness The resulting oil is dried under vacuum

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

Procedure: To a solution of (2S,3S)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid in THF at 0° C. was added BH3-DMS. The reaction was allowed to warm to rt overnight, and then quenched by the careful addition of MeOH. The reaction was concentrated in vacuo to give (2R,3S)-tert-butyl 3-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate as a near colorless oil which was used without further purification. (2R,3S)-tert-Butyl 3-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate was converted to the title compound following the same general protocol for Mitsunobu reaction with phthalimide followed by hydrazine cleavage as described for Example 32 Part V and Part VI. quenched by the careful addition of MeOH The reaction was concentrated in vacuo

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

Procedure: To a solution of (2S,3S)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid in THF at 0° C. was added BH3-DMS. The reaction was allowed to warm to rt overnight, and then quenched by the careful addition of MeOH. The reaction was concentrated in vacuo to give (2R,3S)-tert-butyl 3-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate as a near colorless oil which was used without further purification. (2R,3S)-tert-Butyl 3-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate was converted to the title compound following the same general protocol for Mitsunobu reaction with phthalimide followed by hydrazine cleavage as described for Example 32 Part V and Part VI. quenched by the careful addition of MeOH The reaction was concentrated in vacuo

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

Procedure: To a 0° C. solution of (2R,3S)-tert-butyl 3-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 (99%), 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:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The product from Example 51A (7.73 g, 33.5 mmol) in dry THF (100 mL) was treated with borane-methyl sulfide complex (10 M in THF, 7.4 mL, 74 mmol) dropwise over 10 minutes. The solution was refluxed for 1 hour, cooled to 10-20° C., and methanol was added cautiously until there was no obvious evolution of hydrogen. The mixture was concentrated under reduced pressure and the white residue was stirred with water (50 mL) for 10 minutes and then extracted with ethyl acetate (3×100 mL). The extracts were combined, washed with brine (2×10 mL), dried (Na2SO4), and concentrated to provide the title compound as a white solid (7.24 g, 99%). MS (DCI/NH3) m/z 218 (M+H)+. The solution was refluxed for 1 hour The mixture was concentrated under reduced pressure extracted with ethyl acetate (3×100 mL) washed with brine (2×10 mL) dried (Na2SO4) concentrated