1-O-tert-butyl 2-O-methyl (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate

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

Procedure: To a solution of 1-t-butyl 2-methyl (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (2.15 g, 8.76 mmol) and DABCO (1.57 g, 14.0 mmol) in PhMe (10 mL) at RT was added a solution of brosyl chloride (3.14 g, 12.3 mmol) in PhMe (5 mL). A white precipitate formed, the reaction mixture was stirred for 20 minutes and filtered. The filtrate was partitioned between EtOAc and saturated aqueous NaHCO3; the layers separated; and the organic phase washed with 1 M HCl, water and brine, dried over Na2SO4, filtered and concentrated to afford the title compound as an oil (4.0 g), which was used without further purification. LRMS (M+Na)+ Calcd.: 488; found 488. A white precipitate formed filtered The filtrate was partitioned between EtOAc and saturated aqueous NaHCO3 the layers separated and the organic phase washed with 1 M HCl, water and brine dried over Na2SO4 filtered concentrated

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

Procedure: To a solution of (2S,4S)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (20.0 g) in dichloromethane (500 ml) were added triethylamine (13.5 ml) and methanesulfonyl chloride (7.4 ml) with stirring in an ice bath and the mixture was stirred at the same temperature for 4 hours. The solution was washed successively with diluted hydrochloric acid, saturated aqueous sodium bicarbonate and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to give (2S,4S)-1-t-butoxycarbonyl-4-methylsulfonyloxy-2-methoxycarbonylpyrrolidine (27.7 g) as a pale brown oil. the mixture was stirred at the same temperature for 4 hours The solution was washed successively with diluted hydrochloric acid, saturated aqueous sodium bicarbonate and brine dried over magnesium sulfate The solvent was evaporated in vacuo

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

Procedure: To a solution of (2S,4S)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (20.0 g) in dichloromethane (500 ml) were added triethylamine (13.5 ml) and methanesulfonyl chloride (7.4 ml) with stirring in an ice bath and the mixture was stirred at the same temperature for 4 hours. The solution was washed successively with diluted hydrochloric acid, saturated aqueous sodium bicarbonate and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to give (2S,4S)-1-t-butoxycarbonyl-4-methylsulfonyloxy-2-methoxycarbonylpyrrolidine (27.7 g) as a pale brown oil. the mixture was stirred at the same temperature for 4 hours The solution was washed successively with diluted hydrochloric acid, saturated aqueous sodium bicarbonate and brine dried over magnesium sulfate The solvent was evaporated in vacuo

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

Procedure: To a solution of (2S,4S)-4-benzoyloxy-1-t-butoxycarbonyl-2-methoxycarbonylpyrrolidine (30.0 g) in methanol (600 ml) was added potassium carbonate (11.9 g) and the mixture was stirred at room temperature for 1 hour. The solution was diluted with ethyl acetate (1 l) and washed with water. The organic phase was washed with brine. The aqueous phase was saturated with sodium chloride, extracted with chloroform and washed with brine. The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo to give an oil. The oil was chromatographed on a silica gel (500 g) column with a mixture of n-hexane and ethyl acetate (1:1) as an eluent to give (2S,4S)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (20.7 g) as colorless crystal. washed with water The organic phase was washed with brine extracted with chloroform washed with brine The combined organic extracts were dried over magnesium sulfate evaporated in vacuo to give an oil The oil was chromatographed on a silica gel (500 g) column with a mixture of n-hexane and ethyl acetate (1:1) as an eluent

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

Procedure: To a solution of (2S,4S)-4-benzoyloxy-1-t-butoxycarbonyl-2-methoxycarbonylpyrrolidine (30.0 g) in methanol (600 ml) was added potassium carbonate (11.9 g) and the mixture was stirred at room temperature for 1 hour. The solution was diluted with ethyl acetate (1 l) and washed with water. The organic phase was washed with brine. The aqueous phase was saturated with sodium chloride, extracted with chloroform and washed with brine. The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo to give an oil. The oil was chromatographed on a silica gel (500 g) column with a mixture of n-hexane and ethyl acetate (1:1) as an eluent to give (2S,4S)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (20.7 g) as colorless crystal. washed with water The organic phase was washed with brine extracted with chloroform washed with brine The combined organic extracts were dried over magnesium sulfate evaporated in vacuo to give an oil The oil was chromatographed on a silica gel (500 g) column with a mixture of n-hexane and ethyl acetate (1:1) as an eluent

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

Procedure: To the solution of 2-9-2 (0.228 g, 0.745 mmol), (2S,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (0.219 g, 0.894 mmol) and Triphenylphosphine (0.293 g, 1.117 mmol) in THF (3.72 ml), the Diisopropyl azodicarboxylate (0.217 ml, 1.117 mmol) was added dropwise at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was concentrated. The crude product was purified by combiflash (25 g silica gel, 0-40% ethyl acetate in Hexanes) to give 1-1-1 (0.320 g, 0.600 mmol, 81% yield). MS-ESI, m/z=534.45 (M+1)+. The mixture was concentrated The crude product was purified by combiflash (25 g silica gel, 0-40% ethyl acetate in Hexanes)

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

Procedure: In a manner similar to Step A-3 in Preparative Example 7-A, (2S,4S)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine in dichloromethane is mesylated with triethylamine and methanesulfonylchloride in a nitrogen atmosphere under ice cooling to give (2S,4S)-1-t-butoxycarbonyl-4-methanesulfonyloxy-2-meth-oxycarbonylpyrrolidine. mp. 90.0° to 91.5° C.

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

Procedure: To a solution of (2S,4S)-1-t-butoxycarbonyl-4-formyloxy-2-methoxycarbonylpyrrolidine (5.12 g: 18.7 mmole) in methanol (51.0 ml), aqueous 1N-sodium hydroxide (18.7 ml) is added under ice cooling. The mixture is stirred at the same temperature for 20 minutes to give (2S,4S)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (4.09 g). Yield: 89%. Colorless crystals. NMR δ(CDCl3) ppm: 1.44(d, J=8.2 Hz, 9H), 2.0 to 2.2(m, 1H), 2.2 to 2.5(m, 1H), 3.2 to 3.8(m, 3H), 3.79(d, J=2.8 Hz, 3H), 4.2 to 4.5(m, 2H). IR ν (KBr) cm-1 : 3460, 1728, 1677.

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

Procedure: Under an atmosphere of argon, (2S,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (10 g, 39.5 mmol, Eq: 1.00) was combined with dichloromethane (75 ml) to give a colorless solution. Then at 0° C., 3-nitrobenzene-1-sulfonyl chloride (9.58 g, 41.9 mmol, Eq: 1.06) was added. Also at 0° C., triethylamine (12.0 g, 16.5 ml, 119 mmol, Eq: 3.00) was added dropwise to the reaction mixture. The reaction was stirred for 1.5 h at 0° C. and then for 2 days at room temperature. The reaction mixture was diluted in dichloromethane (200 ml) and then extracted with 2×50 ml HC10.5N, 70 ml satd. NaHCO3 solution and 50 ml satd. NaCl solution. The organic layer was stirred over Na2SO4, filtered and concentrated under reduced pressure. The title compound was obtained as a brown gum (17.25 g, quant., MS (m/e)=431.3 [M+H+]. The product was used in the next step without further purification. to give a colorless solution for 2 days at room temperature extracted with 2×50 ml HC10 The organic layer was stirred over Na2SO4 filtered concentrated under reduced pressure

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

Procedure: The compound was prepared by analogy with Example 217(ii) from N-Boc-cis-4-hydroxy-L-proline methylester and 3,4-dichlorophenol.

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

Procedure: To a solution of (2S,4S)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (20.0 g) in dichloromethane (500 ml) were added triethylamine (13.5 ml) and methanesulfonyl chloride (7.4 ml) with stirring in an ice bath and the mixture was stirred at the same temperature for 4 hours. The solution was washed successively with diluted hydrochloric acid, saturated aqueous sodium bicarbonate and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to give (2S,4S)-1-t-butoxycarbonyl-4-methylsulfonyloxy-2-methoxycarbonylpyrrolidine (27.7 g) as a pale brown oil. the mixture was stirred at the same temperature for 4 hours The solution was washed successively with diluted hydrochloric acid, saturated aqueous sodium bicarbonate and brine dried over magnesium sulfate The solvent was evaporated in vacuo

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

Procedure: To a solution of (2S,4S)-4-benzoyloxy-1-t-butoxycarbonyl-2-methoxycarbonylpyrrolidine (30.0 g) in methanol (600 ml) was added potassium carbonate (11.9 g) and the mixture was stirred at room temperature for 1 hour. The solution was diluted with ethyl acetate (1 l) and washed with water. The organic phase was washed with brine. The aqueous phase was saturated with sodium chloride, extracted with chloroform and washed with brine. The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo to give an oil. The oil was chromatographed on a silica gel (500 g) column with a mixture of n-hexane and ethyl acetate (1:1) as an eluent to give (2S,4S)-1-t-butoxycarbonyl-4-hydroxy-2- methoxycarbonylpyrrolidine (20.7 g) as colorless crystal. washed with water The organic phase was washed with brine extracted with chloroform washed with brine The combined organic extracts were dried over magnesium sulfate evaporated in vacuo to give an oil The oil was chromatographed on a silica gel (500 g) column with a mixture of n-hexane and ethyl acetate (1:1) as an eluent