(S)-2-Iodomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

Conditions: temp:-36.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under a nitrogen atmosphere, a solution of vinylmagnesium bromide, 1.0 M in tetrahydrofuran (2.0 mL, 2.0 mmol) was slowly added to a suspension of copper(I) iodide (244.9 mg, 1.28 mmol) in dry diethyl ether (10 mL) at −78° C. Upon completion of the addition, the mixture was warmed to −36° C. for 5 min and was then cooled to −78° C. A solution of (2S)-N-(tert-butoxycarbonyl)-2-(iodomethyl)pyrrolidine (200.0 mg, 0.64 mmol) in dry diethyl ether (5 mL) was added over a period of 10 min. The reaction mixture was warmed to −36° C. and was stirred at −36° C. for 6 h. The resulting dark mixture was treated with saturated aqueous NH4Cl solution (5 mL) and was stirred while warming to ambient temperature. The reaction mixture was extracted with diethyl ether (4×10 mL). The combined ether extracts were dried (Na2SO4), filtered and concentrated under vacuum to yield a pale-yellow oil (200 mg). The product was purified by column chromatography, eluting with hexane:ethyl acetate (1:1). Fractions containing the product were combined and concentrated under vacuum to afford 100 mg (73.6%) of an oil. Upon completion of the addition was then cooled to −78° C The reaction mixture was warmed to −36° C. was stirred while warming to ambient temperature The reaction mixture was extracted with diethyl ether (4×10 mL) The combined ether extracts were dried (Na2SO4) filtered concentrated under vacuum

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

Procedure: Under a nitrogen atmosphere, a solution of diethyl azodicarboxylate (4.699 g, 26.98 mmol) in dry tetrahydrofuran (THF) (15 mL) was added drop-wise to an ice-cold stirring solution of (2S)-N-(tert-butoxycarbonyl)-2-(hydroxymethyl)pyrrolidine (5.37 g, 26.7 mmol), iodine (3.42 g, 13.5 mmol) and triphenylphosphine (7.069 g, 26.95 mmol) in dry THF (50 mL). The mixture was stirred and allowed to warm to ambient temperature overnight. The mixture was concentrated on a rotary evaporator and then the residue was stirred with 5% aqueous Na2S2O3 (50 mL). After stirring for 30 min, the mixture was extracted with dichloromethane (4×25 mL). The combined dichloromethane extracts were dried (Na2SO4), filtered and concentrated. The residue was repeatedly crystallized (three to four times) from dry ether and finally from heptane to give 3.20 g (38.6%) of product. The mixture was concentrated on a rotary evaporator the residue was stirred with 5% aqueous Na2S2O3 (50 mL) After stirring for 30 min the mixture was extracted with dichloromethane (4×25 mL) The combined dichloromethane extracts were dried (Na2SO4) filtered concentrated The residue was repeatedly crystallized (three to four times) from dry ether

Conditions: temp:-36.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under a nitrogen atmosphere, a solution of vinylmagnesium bromide, 1.0 M in tetrahydrofuran (2.0 mL, 2.0 mmol) was slowly added to a suspension of copper(I) iodide (244.9 mg, 1.28 mmol) in dry diethyl ether (10 mL) at −78° C. Upon completion of the addition, the mixture was warmed to −36° C. for 5 min and was then cooled to −78° C. A solution of (2S)-N-(tert-butoxycarbonyl)-2-(iodomethyl)pyrrolidine (200.0 mg, 0.64 mmol) in dry diethyl ether (5 mL) was added over a period of 10 min. The reaction mixture was warmed to −36° C. and was stirred at −36° C. for 6 h. The resulting dark mixture was treated with saturated aqueous NH4Cl solution (5 mL) and was stirred while warming to ambient temperature. The reaction mixture was extracted with diethyl ether (4×10 mL). The combined ether extracts were dried (Na2SO4), filtered and concentrated under vacuum to yield a pale-yellow oil (200 mg). The product was purified by column chromatography, eluting with hexane:ethyl acetate (1:1). Fractions containing the product were combined and concentrated under vacuum to afford 100 mg (73.6%) of an oil. Upon completion of the addition was then cooled to −78° C The reaction mixture was warmed to −36° C. was stirred while warming to ambient temperature The reaction mixture was extracted with diethyl ether (4×10 mL) The combined ether extracts were dried (Na2SO4) filtered concentrated under vacuum

Conditions: temp:-36.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under a nitrogen atmosphere, a solution of vinylmagnesium bromide, 1.0 M in tetrahydrofuran (2.0 mL, 2.0 mmol) was slowly added to a suspension of copper(I) iodide (244.9 mg, 1.28 mmol) in dry diethyl ether (10 mL) at −78° C. Upon completion of the addition, the mixture was warmed to −36° C. for 5 min and was then cooled to −78° C. A solution of (2S)-N-(tert-butoxycarbonyl)-2-(iodomethyl)pyrrolidine (200.0 mg, 0.64 mmol) in dry diethyl ether (5 mL) was added over a period of 10 min. The reaction mixture was warmed to −36° C. and was stirred at −36° C. for 6 h. The resulting dark mixture was treated with saturated aqueous NH4Cl solution (5 mL) and was stirred while warming to ambient temperature. The reaction mixture was extracted with diethyl ether (4×10 mL). The combined ether extracts were dried (Na2SO4), filtered and concentrated under vacuum to yield a pale-yellow oil (200 mg). The product was purified by column chromatography, eluting with hexane:ethyl acetate (1:1). Fractions containing the product were combined and concentrated under vacuum to afford 100 mg (73.6%) of an oil. Upon completion of the addition was then cooled to −78° C The reaction mixture was warmed to −36° C. was stirred while warming to ambient temperature The reaction mixture was extracted with diethyl ether (4×10 mL) The combined ether extracts were dried (Na2SO4) filtered concentrated under vacuum

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

Procedure: Under a nitrogen atmosphere, a solution of diethyl azodicarboxylate (4.699 g, 26.98 mmol) in dry tetrahydrofuran (THF) (15 mL) was added drop-wise to an ice-cold stirring solution of (2S)-N-(tert-butoxycarbonyl)-2-(hydroxymethyl)pyrrolidine (5.37 g, 26.7 mmol), iodine (3.42 g, 13.5 mmol) and triphenylphosphine (7.069 g, 26.95 mmol) in dry THF (50 mL). The mixture was stirred and allowed to warm to ambient temperature overnight. The mixture was concentrated on a rotary evaporator and then the residue was stirred with 5% aqueous Na2S2O3 (50 mL). After stirring for 30 min, the mixture was extracted with dichloromethane (4×25 mL). The combined dichloromethane extracts were dried (Na2SO4), filtered and concentrated. The residue was repeatedly crystallized (three to four times) from dry ether and finally from heptane to give 3.20 g (38.6%) of product. The mixture was concentrated on a rotary evaporator the residue was stirred with 5% aqueous Na2S2O3 (50 mL) After stirring for 30 min the mixture was extracted with dichloromethane (4×25 mL) The combined dichloromethane extracts were dried (Na2SO4) filtered concentrated The residue was repeatedly crystallized (three to four times) from dry ether

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Diisopropylamine (764 uL, 5.4 mmol) was dissolved in THF (15 mL) under nitrogen and cooled to −70° C. Then a 1.6 M solution of butyllithium in hexane (3.4 mL, 5.4 mmol) was added and stirring at −70° C. was continued for 15 min. Then a solution of (3-chloro-phenyl)-trimethylsilanyloxy-acetonitrile (1.18 g, 4.9 mmol) in THF (5 mL) was added and stirring at −70° C. was continued for 30 min, producing a yellow color. Then a solution of (S)-2-iodomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.53 g, 4.9 mmol) in THF (5 mL) was added and stirring at −70° C. was continued for 5 h and then allowed to warm up to 20° C. and stirred overnight. The mixture was extracted with AcOEt, 1 M citric acid, and 50% NaCl. The crude product was purified by flash chromatography on silica gel with a heptane/AcOEt gradient 0-15%. One obtained 500 mg (31%) of a yellow oil. MS: m/z=224 [M+]. stirring at −70° C. was continued for 30 min producing a yellow color stirring at −70° C. was continued for 5 h to warm up to 20° C. stirred overnight The mixture was extracted with AcOEt, 1 M citric acid, and 50% NaCl The crude product was purified by flash chromatography on silica gel with a heptane/AcOEt gradient 0-15%

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

Procedure: 1-Ethylpiperidine hypophosphite (30 g, 168 mmol) were weighed into the reaction flask under an inert gas, and methylene chloride (100 ml) was added. The solution was cooled with ice-water and 2,3,4,5,6-pentafluorophenyl 1-ethylenesulfonate (5.06 g, 18.5 mmol) [Org. Lett.; 2002; 4(15); 2549-2551] and (S)-tert-butyl 2-(iodomethyl)pyrrolidine-1-carboxylate (5.22 g, 16.8 mmol) was added at 10° C. Triethylborane solution (1.6 ml, 1 mol/l) was added and compressed air was then passed through the mixture for 5 sec. After stirring for min the addition of triethylborane solution-compressed air was repeated with the same amount. The cooling bath was removed, the mixture was stirred for 10 min and the reaction mixture was then washed with water (20 ml) and saturated sodium chloride solution (20 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with hexane/diethyl ether (2:1). Yield: 2.81 g (36%) was added was added at 10° C The cooling bath was removed the mixture was stirred for 10 min the reaction mixture was then washed with water (20 ml) and saturated sodium chloride solution (20 ml) dried over sodium sulfate concentrated in vacuo The crude product was purified by column chromatography (silica gel) with hexane/diethyl ether (2:1)

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

Procedure: (S)-(−)-N-Boc-prolinol (10 g, 49.7 mmol), imidazole (6.76 g, 99.4 mmol) and triphenylphosphine (19.5 g, 74.5 mmol) were dissolved in diethyl ether (210 ml) and acetonitrile (80 ml) and the solution was cooled to 0° C. under an inert gas. Iodine (17.7 g, 70 mmol) was added in portions at this temperature. The yellow suspension was stirred for 15 h, and warmed to room temperature during this procedure. Addition of sodium thiosulfate solution (50 ml, 5 mol/l), stir for 5 min, the phases were separated. The aqueous phase was extracted with diethyl ether (2×100 ml) and the combined organic phases were washed with copper sulfate solution (30 ml, 5%) and sodium chloride solution (30 ml, saturated), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with hexane/diethyl ether (6:1). Yield: 10.57 g (68%) stir for 5 min the phases were separated The aqueous phase was extracted with diethyl ether (2×100 ml) the combined organic phases were washed with copper sulfate solution (30 ml, 5%) and sodium chloride solution (30 ml, saturated) dried over sodium sulfate concentrated in vacuo The crude product was purified by column chromatography (silica gel) with hexane/diethyl ether (6:1)

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

Procedure: A heterogenous reaction mixture of 2-(S)-iodomethyl-pyrrolidine-1-carboxylic acid tert butyl ester (compound (4) obtained from above, 25 g, 0.08 mol), triethylamine (11.2 mL, 8.12 g, 0.08 mol) in methanol (250 mL) and 5% palladium on carbon (2.5 g, 10 wt %, Pd/C) was allowed to react at room temperature under a blanket of hydrogen gas overnight and until HPLC showed less than 1% starting material (˜7 hours). The reaction mixture was filtered and the filtrate was concentrated to a residue. The residue was dissolved in distilled water (100 mL) and ethyl acetate (100 mL). The organic layer was separated and the aqueous layer was re-extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with 1 M aqueous H3PO4 (2×100 mL) followed by saturated NaHCO3 (233 100 mL), dried over MgSO4, filtered, and concentrated to leave an oily residual product (12.78 g, 85.9% yield). 1H NMR (CDCl3): δ 1.16 (d, 3H, CH3), 1.47 (s, 9H, 3×CH3), 1.50–1.82 (m, 2H, CH2), 1.84–2.03 (m, 2H, CH2 ), 3.34 (m, 2H, CH2) and 3.86 (m, 1H, CH); [M+H]+ at m/z 186. material (˜7 hours) The reaction mixture was filtered the filtrate was concentrated to a residue The residue was dissolved in distilled water (100 mL) The organic layer was separated the aqueous layer was re-extracted with ethyl acetate (2×50 mL) The combined organic layer was washed with 1 M aqueous H3PO4 (2×100 mL) dried over MgSO4 filtered concentrated

Conditions: temp:62.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-(S)-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (compound (3) obtained from above, 30 g, 0.10 mol) in anhydrous tetrahydrofuran (600 mL) was cooled to 0° C. Lithium iodide (144 g, 1 mol) was added to the cold reaction mixture as a solid in portions while maintaining the reaction temperature at below 30° C. The reaction mixture was warmed to 62° C. until HPLC showed less than 2% starting material. The reaction mixture was quenched with 10% aqueous sodium thiosulfate (300 mL). Ethyl acetate (600 mL) was added to reaction mixture. The organic layer was separated. The aqueous layer was re-extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine (2×100 mL), dried over MgSO4, filtered, and concentrated to leave an oily residual product (26.3 g, 78.6% yield). 1H NMR (CDCl3): δ 1.46 (d, 3H, CH3), 1.48 (d, 6H, 2×CH3), 1.792.14 (m, 4H, 2×CH2), 3.14–3.52 (m, 4H, 2×CH2) and 3.88 (m, 1H, CH); [M+H]+ at m/z 312. while maintaining the reaction temperature at below 30° C The reaction mixture was quenched with 10% aqueous sodium thiosulfate (300 mL) Ethyl acetate (600 mL) was added to reaction mixture The organic layer was separated The aqueous layer was re-extracted with ethyl acetate (3×50 mL) The combined organic layer was washed with brine (2×100 mL) dried over MgSO4 filtered concentrated