(3R,4R)-(-)-1-BENZYL-3,4-PYRROLIDINDIOL

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

Procedure: To a 1,4-dioxane (20 mL) solution of 1,4-di-O-tosyl-D-threitol (9.15 g, 21.25 mmol), benzylamine (9.29 mL, 85.0 mmol) was added, and the mixture was heated to reflux under a nitrogen stream for 4 days while stirring. The reaction liquor was returned to room temperature, and then a saturated aqueous solution of sodium hydrogen carbonate (50 mL) was added. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography using silica gel [NH(basic)-silica gel 100 g, ethyl acetate to chloroform/methanol (10/1)], to obtain the title compound (1.88 g, 46%) as an oily matter. the mixture was heated to reflux under a nitrogen stream for 4 days was returned to room temperature The mixture was extracted with ethyl acetate The extract was washed with saturated brine dried over anhydrous sodium sulfate concentrated under reduced pressure The obtained residue was purified by column chromatography

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

Procedure: Boron trifluoride ethyl etherate (36 ml, 0.29 mol) in diglyme (150 ml) was cooled to 0+ C. (3S,4S)-1-Benzyl-3,4-dihydroxy-2,5-dioxopyrrolidine (16 g, 72 mmol) and sodium borohydride were added slowly. The mixture was stirred at 70° C. for 2 hours. 6 N hydrochloric acid (100 ml) was added slowly and the mixture was heated at 70° C. for 15 minutes. Sodium fluoride (44.5 g, 1 mol) was added and the mixture was heated at reflux temperature for 1/2 hour. The mixture was cooled to room temperature. 20% Aqueous sodium hydroxide (85 ml) was added and the resulting mixture was filtered. The organic phase was isolated and evaporated to dryness. The residue was partitioned between water and diethyl ether. The water phase was extracted with ether (4×500 ml). The collected organic phases were dried over magnesium sulphate and evaporated to dryness. Recrystallization from ethyl acetate (25 ml) gave (3R,4R)-1-benzyl-3,4-pyrrolidinediol (12.3 g, yield: 88%) as white crystals. the mixture was heated at 70° C. for 15 minutes the mixture was heated at reflux temperature for 1/2 hour The mixture was cooled to room temperature the resulting mixture was filtered The organic phase was isolated evaporated to dryness The residue was partitioned between water and diethyl ether The water phase was extracted with ether (4×500 ml) The collected organic phases were dried over magnesium sulphate evaporated to dryness Recrystallization from ethyl acetate (25 ml)

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

Procedure: Boron trifluoride ethyl etherate (36 ml, 0.29 mol) in diglyme (150 ml) was cooled to 0+ C. (3S,4S)-1-Benzyl-3,4-dihydroxy-2,5-dioxopyrrolidine (16 g, 72 mmol) and sodium borohydride were added slowly. The mixture was stirred at 70° C. for 2 hours. 6 N hydrochloric acid (100 ml) was added slowly and the mixture was heated at 70° C. for 15 minutes. Sodium fluoride (44.5 g, 1 mol) was added and the mixture was heated at reflux temperature for 1/2 hour. The mixture was cooled to room temperature. 20% Aqueous sodium hydroxide (85 ml) was added and the resulting mixture was filtered. The organic phase was isolated and evaporated to dryness. The residue was partitioned between water and diethyl ether. The water phase was extracted with ether (4×500 ml). The collected organic phases were dried over magnesium sulphate and evaporated to dryness. Recrystallization from ethyl acetate (25 ml) gave (3R,4R)-1-benzyl-3,4-pyrrolidinediol (12.3 g, yield: 88%) as white crystals. the mixture was heated at 70° C. for 15 minutes the mixture was heated at reflux temperature for 1/2 hour The mixture was cooled to room temperature the resulting mixture was filtered The organic phase was isolated evaporated to dryness The residue was partitioned between water and diethyl ether The water phase was extracted with ether (4×500 ml) The collected organic phases were dried over magnesium sulphate evaporated to dryness Recrystallization from ethyl acetate (25 ml)

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

Procedure: To an ice-cold (0-5° C.) solution of the product from Step 2 (5.27 g, 27.3 mmol) and TEA (8.27 g, 81.9 mmol) in dichloromethane (50 mL), was added methanesulfonyl chloride (6.87 g, 60.0 mmol) over a period of 30 minutes. After stirring at RT overnight, the reaction mixture was washed with water. The organic layer was dried (sodium sulfate), filtered, and concentrated to give the crude product which was purified over a silica column (5:95 EtOAc/hexane) to obtain pure product (6.44 g, 67.6%). 1H NMR (300 MHz, CDCl3) δ 7.32-7.26 (5H, m), 5.14 (2H, m), 3.65 (2H, s), 3.15-3.08 (2H, m), 3.08 (6H, s), 2.76 (2H, dd). MS m/z 350 (MH+). the reaction mixture was washed with water The organic layer was dried (sodium sulfate) filtered concentrated to give the crude product which was purified over a silica column (5:95 EtOAc/hexane)

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

Procedure: To a mechanically stirred and cooled solution (0° C.) of the product from Step 1 (50 g, 0.23 mol) in dry THF (1.24 L) was added sodium aluminum hydride bis-(methoxyethoxide) (289 mL of a 65% Red-Al®/Toluene solution, 0.95 mol) under a nitrogen atmosphere at such a rate that the internal temperature did not exceed 20° C. The reaction mixture was allowed stir at room temperature for 2 h after the addition was complete. The reaction mixture was slowly poured into ice water (1.0 L) with stirring to quench the reaction. After warming to room temperature, 30% ammonium hydroxide (100 mL) was added followed by EtOAc (1.5 L) and this mixture was stirred for 16 h. The suspension was filtered through diatomaceous earth and the solids were washed with EtOAc. The filtrate layers were separated and the organic phase was dried over sodium sulfate and concentrated to afford a syrup. Dissolution in methylene chloride and concentration affords a white solid that is collected and dried (43.7 g, 86%). 1H NMR (300 MHz, CDCl3) δ 7.36-7.23 (5H, m), 6.23 (2H, m), 4.65 (1H, m), 4.15-4.00 (3H, m), 3.62-3.49 (1H, dd), 3.33 (1H, dd), 3.14 (1H, dd), 2.94 (1H dd). MS m/z 194 (MH+). did not exceed 20° C The reaction mixture was allowed stir at room temperature for 2 h after the addition with stirring to quench the reaction this mixture was stirred for 16 h The suspension was filtered through diatomaceous earth the solids were washed with EtOAc The filtrate layers were separated the organic phase was dried over sodium sulfate concentrated to afford a syrup concentration affords a white solid that is collected dried (43.7 g, 86%)

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

Procedure: To an ice-cold (0-5° C.) solution of the product from Step 2 (5.27 g, 27.3 mmol) and TEA (8.27 g, 81.9 mmol) in dichloromethane (50 mL), was added methanesulfonyl chloride (6.87 g, 60.0 mmol) over a period of 30 minutes. After stirring at RT overnight, the reaction mixture was washed with water. The organic layer was dried (sodium sulfate), filtered, and concentrated to give the crude product which was purified over a silica column (5:95 EtOAc/hexane) to obtain pure product (6.44 g, 67.6%). 1H NMR (400 MHz, CDCl3) δ 7.32-7.26 (5H, m), 5.14 (2H, m), 3.65 (2H, s), 3.15-3.08 (2H, m), 3.08 (6H, s), 2.76 (2H, dd). MS m/z 350 (MH+). the reaction mixture was washed with water The organic layer was dried (sodium sulfate) filtered concentrated to give the crude product which was purified over a silica column (5:95 EtOAc/hexane)

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

Procedure: To a mechanically stirred and cooled solution (0° C.) of the product from Step 1 (50 g, 0.23 mol) in dry THF (1.24 L) was added sodium aluminum hydride bis-(methoxyethoxide) (289 mL of a 65% Red-A;®/Toluene solution, 0.95 mol) under a nitrogen atmosphere at such a rate that the internal temperature did not exceed 20° C. The reaction mixture was allowed stir at room temperature for 2 h after the addition was complete. The reaction mixture was slowly poured into ice water (1.0 L) with stirring to quench the reaction. After warming to room temperature, 30% ammonium hydroxide (100 mL) was added followed by EtOAc (1.5 L) and this mixture was stirred for 16 h. The suspension was filtered through diatomaceous earth and the solids were washed with EtOAc. The filtrate layers were separated and the organic phase was dried over sodium sulfate and concentrated to afford a syrup. Dissolution in dichloromethane and concentration affords a white solid that is collected and dried (43.7 g, 86%). 1H NMR (400 MHz, CDCl3) δ 7.36-7.23 (5H, m), 6.23 (2H, m), 4.65 (1H, m), 4.15-4.00 (3H, m), 3.62-3.49 (1H, dd), 3.33 (1H, dd), 3.14 (1H, dd), 2.94 (1H dd). MS m/z 194 (MH+). did not exceed 20° C The reaction mixture was allowed stir at room temperature for 2 h after the addition with stirring to quench the reaction this mixture was stirred for 16 h The suspension was filtered through diatomaceous earth the solids were washed with EtOAc The filtrate layers were separated the organic phase was dried over sodium sulfate concentrated to afford a syrup concentration affords a white solid that is collected dried (43.7 g, 86%)

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

Procedure: Compound VI-15 (251 mg, 62.7%) was obtained in the same manner as that in Reference Example 1, by using (3R,4R)-1-benzylpyrrolidine-3,4-diol (Diverchim S. A.; 103 mg, 0.534 mmol) and (Z)-icos-11-enyl methanesulfonate (Nu-Chek Prep, Inc; 500 mg, 1.34 mmol).

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

Procedure: Compound VI-14 (244 mg, 60.8%) was obtained in the same manner as that in Reference Example 1, by using (3R,4R)-1-benzylpyrrolidine-3,4-diol (Diverchim S. A.; 112 mg, 0.577 mmol) and (Z)-octadec-11-enyl methanesulfonate (Nu-Chek Prep, Inc; 500 mg, 1.44 mmol). Compound VI-14 (244 mg, 60.8%) was obtained in the same manner as that in Reference Example 1

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

Procedure: Compound VI-13 (119 mg, 49.5%) was obtained in the same manner as that in Reference Example 1, by using (3R,4R)-1-benzylpyrrolidine-3,4-diol (Diverchim S. A.; 80.0 mg, 0.414 mmol) and (Z)-tetradec-9-enyl methanesulfonate (Nu-Chek Prep, Inc; 301 mg, 1.04 mmol). Compound VI-13 (119 mg, 49.5%) was obtained in the same manner as that in Reference Example 1

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

Procedure: Compound VI-12 (319 mg, 88.3%) was obtained in the same manner as that in Reference Example 5, by using (3R,4R)-1-benzylpyrrolidine-3,4-diol (Diverchim S. A.; 100 mg, 0.517 mmol) and octadecyl methanesulfonate (Nu-Chek Prep, Inc; 451 mg, 1.29 mmol). Compound VI-12 (319 mg, 88.3%) was obtained in the same manner as that in Reference Example 5

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

Procedure: Compound VI-11 (324 mg, 97.6%) was obtained in the same manner as that in Reference Example 5, by using (3R,4R)-1-benzylpyrrolidine-3,4-diol (Diverchim S. A.; 100 mg, 0.517 mmol) and hexadecyl methanesulfonate (Nu-Chek Prep, Inc; 415 mg, 1.29 mmol). Compound VI-11 (324 mg, 97.6%) was obtained in the same manner as that in Reference Example 5