tert-butyl N-[(3R,6S)-6-(hydroxymethyl)oxan-3-yl]carbamate

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

Procedure: In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to an ice-cold solution of (3R,6S)-6-hydroxymethyl-tetrahydro-2H-pyran-3-yl carbamic acid tert-butyl ester (328 mg, 1.40 mmol, H. S. Overkleeft et al. Eur. J. Org. Chem. 2003, 2418), triphenylphoshine on polystyrene (6.16 mmol) and imidazole (203 mg, 2.95 mmol) in dry CH2Cl2 (14 mL) was added iodine (891 mg, 3.48 mmol). The reaction mixture was warmed to rt and stirred at this temperature until completion of the reaction. The mixture was then filtered, CH2Cl2 removed under reduced pressure. The residue was redissolved in EA, successively washed with 10% aq. Na2SO3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by FC, the iodide was redissolved in CH3CN (15 mL) and treated with pyrrolidine (1.13 mL, 13.57 mmol) and K2CO3 (750 mg, 5.43 mmol). The reaction mixture was stirred at 85° C. until completion of the reaction, filtered and concentrated under reduced pressure. The amine was purified by FC (hept-EA-acetone, 1:0:0->0:0:1) and then the Boc group was removed by treatment with HCl (4.0 M in dioxane, 9 eq.) in dry CH2Cl2 (2 mL). The title compound was obtained after trituration in hot EA/acetone/MeOH as an off-white solid. LC-MS-conditions 01: tR=0.15 min; [M+H]+=185.06. The mixture was then filtered CH2Cl2 removed under reduced pressure The residue was redissolved in EA successively washed with 10% aq. Na2SO3 and brine dried over Na2SO4 filtered concentrated under reduced pressure After purification by FC the iodide was redissolved in CH3CN (15 mL) The reaction mixture was stirred at 85° C. until completion of the reaction filtered concentrated under reduced pressure The amine was purified by FC (hept-EA-acetone, 1:0:0->0:0:1)

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

Procedure: In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to an ice-cold solution of (3R,6S)-6-hydroxymethyl-tetrahydro-2H-pyran-3-yl carbamic acid tert-butyl ester (328 mg, 1.40 mmol, H. S. Overkleeft et al. Eur. J. Org. Chem. 2003, 2418), triphenylphoshine on polystyrene (6.16 mmol) and imidazole (203 mg, 2.95 mmol) in dry CH2Cl2 (14 mL) was added iodine (891 mg, 3.48 mmol). The reaction mixture was warmed to rt and stirred at this temperature until completion of the reaction. The mixture was then filtered, CH2Cl2 removed under reduced pressure. The residue was redissolved in EA, successively washed with 10% aq. Na2SO3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by FC, the iodide was redissolved in CH3CN (15 mL) and treated with pyrrolidine (1.13 mL, 13.57 mmol) and K2CO3 (750 mg, 5.43 mmol). The reaction mixture was stirred at 85° C. until completion of the reaction, filtered and concentrated under reduced pressure. The amine was purified by FC (hept-EA-acetone, 1:0:0->0:0:1) and then the Boc group was removed by treatment with HCl (4.0 M in dioxane, 9 eq.) in dry CH2Cl2 (2 mL). The title compound was obtained after trituration in hot EA/acetone/MeOH as an off-white solid. LC-MS-conditions 01: tR=0.15 min; [M+H]+=185.06. The mixture was then filtered CH2Cl2 removed under reduced pressure The residue was redissolved in EA successively washed with 10% aq. Na2SO3 and brine dried over Na2SO4 filtered concentrated under reduced pressure After purification by FC the iodide was redissolved in CH3CN (15 mL) The reaction mixture was stirred at 85° C. until completion of the reaction filtered concentrated under reduced pressure The amine was purified by FC (hept-EA-acetone, 1:0:0->0:0:1)

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

Procedure: To a solution of oxalyl chloride (3.5 ml) in DCM (25 ml) cooled to −78° C., was added drop wise a solution of DMSO (3.5 ml) in DCM (25 ml). After 15 minutes stirring, a solution of (3R,6S)-(6-hydroxymethyl-tetrahydro-pyran-3-yl)-carbamic acid tert-butyl ester (prepared as described in Eur. J. Org. Chem. (2003), 2418-2427; 3 g) in DCM (25 ml) was added drop wise. The reaction was stirred 1 h and a solution of triethylamine (15 ml) in DCM (15 ml) was added dropwise. The reaction proceeded for 1 hour, with warming to 0° C. Saturated sodium bicarbonate (50 ml) was added. The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed (Hex/EtOAc 1:2) to afford the title aldehyde (2.5 g) as a colorless solid. The reaction was stirred 1 h The reaction proceeded for 1 hour The organic layer was separated dried over sodium sulfate filtered concentrated in vacuo The residue was chromatographed (Hex/EtOAc 1:2)

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

Procedure: To a solution of oxalyl chloride (3.5 ml) in DCM (25 ml) cooled to −78° C., was added drop wise a solution of DMSO (3.5 ml) in DCM (25 ml). After 15 minutes stirring, a solution of (3R,6S)-(6-hydroxymethyl-tetrahydro-pyran-3-yl)-carbamic acid tert-butyl ester (prepared as described in Eur. J. Org. Chem. (2003), 2418-2427; 3 g) in DCM (25 ml) was added drop wise. The reaction was stirred 1 h and a solution of triethylamine (15 ml) in DCM (15 ml) was added dropwise. The reaction proceeded for 1 hour, with warming to 0° C. Saturated sodium bicarbonate (50 ml) was added. The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed (Hex/EtOAc 1:2) to afford the title aldehyde (2.5 g) as a colorless solid. The reaction was stirred 1 h The reaction proceeded for 1 hour The organic layer was separated dried over sodium sulfate filtered concentrated in vacuo The residue was chromatographed (Hex/EtOAc 1:2)

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

Procedure: 1,5-Anhydro-2-[(tert-butoxycarbonyl)amino]-2,3,4-trideoxy-D-erythro-hexitol (Eur. J. Org. Chem., 2003, 2418-2427) (6.00 g, 0.03 mol) was dissolved in methanol (20 ml), 4N hydrochloric acid/1,4-dioxane solution (60 ml) was added and the resulting mixture was stirred at room temperature for 1 hour. The reaction solvent was evaporated under reduced pressure to give 4.5 g (100%) of the title compound as a colorless solid. The reaction solvent was evaporated under reduced pressure

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

Procedure: 1,5-Anhydro-2-[(tert-butoxycarbonyl)amino]-2,3,4-trideoxy-D-erythro-hexitol (Eur. J. Org. Chem., 2003, 2418-2427) (6.00 g, 0.03 mol) was dissolved in methanol (20 ml), 4N hydrochloric acid/1,4-dioxane solution (60 ml) was added and the resulting mixture was stirred at room temperature for 1 hour. The reaction solvent was evaporated under reduced pressure to give 4.5 g (100%) of the title compound as a colorless solid. The reaction solvent was evaporated under reduced pressure

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

Procedure: To a solution of (3R,6S)-(6-hydroxymethyl-tetrahydro-pyran-3-yl)-carbamic acid tert-butyl ester (37.5 g, 162.13 mmol) in DCM (310 mL) cooled to −10° C. was added DIPEA (84.75 mL, 495.06 mmol). Then a solution of Pyr.SO3 complex (50%, 69.47 g, 218.25 mmol) in DMSO (225 mL) was slowly added. The reaction mixture was stirred for 2 h at 0° C. The reaction mixture was partitioned between water (150 mL) and DCM (220 mL). The two layers were separated and the aq. layer was extracted twice with DCM (2×150 mL). The combined org. layers were dried over Na2SO4, filtered and concentrated to dryness. The residue was co-evaporated 3 times with toluene and purified over a short pad of silica gel (EA-Hept. 2-1) to afford the title aldehyde as a white solid (33.58 g, 90% yield). The reaction mixture was partitioned between water (150 mL) and DCM (220 mL) The two layers were separated the aq. layer was extracted twice with DCM (2×150 mL) layers were dried over Na2SO4 filtered concentrated to dryness purified over a short pad of silica gel (EA-Hept. 2-1)

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

Procedure: In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to an ice-cold solution of (3R,6S)-6-hydroxymethyl-tetrahydro-2H-pyran-3-yl carbamic acid tert-butyl ester (328 mg, 1.40 mmol, H. S. Overkleeft et al. Eur. J. Org. Chem. 2003, 2418), triphenylphoshine on polystyrene (6.16 mmol) and imidazole (203 mg, 2.95 mmol) in dry CH2Cl2 (14 mL) was added iodine (891 mg, 3.48 mmol). The reaction mixture was warmed to rt and stirred at this temperature until completion of the reaction. The mixture was then filtered, CH2Cl2 removed under reduced pressure. The residue was redissolved in EA, successively washed with 10% aq. Na2SO3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by FC, the iodide was redissolved in CH3CN (15 mL) and treated with pyrrolidine (1.13 mL, 13.57 mmol) and K2CO3 (750 mg, 5.43 mmol). The reaction mixture was stirred at 85° C. until completion of the reaction, filtered and concentrated under reduced pressure. The amine was purified by FC (hept-EA-acetone, 1:0:0->0:0:1) and then the Boc group was removed by treatment with HCl (4.0 M in dioxane, 9 eq.) in dry CH2Cl2 (2 mL). The title compound was obtained after trituration in hot EA/acetone/MeOH as an off-white solid. LC-MS-conditions 01: tR=0.15 min; [M+H]+=185.06. The mixture was then filtered CH2Cl2 removed under reduced pressure The residue was redissolved in EA successively washed with 10% aq. Na2SO3 and brine dried over Na2SO4 filtered concentrated under reduced pressure After purification by FC the iodide was redissolved in CH3CN (15 mL) The reaction mixture was stirred at 85° C. until completion of the reaction filtered concentrated under reduced pressure The amine was purified by FC (hept-EA-acetone, 1:0:0->0:0:1)

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

Procedure: To a solution of oxalyl chloride (3.5 ml) in DCM (25 ml) cooled to −78° C., was added drop wise a solution of DMSO (3.5 ml) in DCM (25 ml). After 15 minutes stirring, a solution of (3R,6S)-(6-hydroxymethyl-tetrahydro-pyran-3-yl)-carbamic acid tert-butyl ester (prepared as described in Eur. J. Org. Chem. (2003), 2418-2427; 3 g) in DCM (25 ml) was added drop wise. The reaction was stirred 1 h and a solution of triethylamine (15 ml) in DCM (15 ml) was added dropwise. The reaction proceeded for 1 hour, with warming to 0° C. Saturated sodium bicarbonate (50 ml) was added. The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed (Hex/EtOAc 1:2) to afford the title aldehyde (2.5 g) as a colorless solid. The reaction was stirred 1 h The reaction proceeded for 1 hour The organic layer was separated dried over sodium sulfate filtered concentrated in vacuo The residue was chromatographed (Hex/EtOAc 1:2)

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

Procedure: 1,5-Anhydro-2-[(tert-butoxycarbonyl)amino]-2,3,4-trideoxy-D-erythro-hexitol (Eur. J. Org. Chem., 2003, 2418-2427) (6.00 g, 0.03 mol) was dissolved in methanol (20 ml), 4N hydrochloric acid/1,4-dioxane solution (60 ml) was added and the resulting mixture was stirred at room temperature for 1 hour. The reaction solvent was evaporated under reduced pressure to give 4.5 g (100%) of the title compound as a colorless solid. The reaction solvent was evaporated under reduced pressure