[(2R,3R)-3-phenyloxiran-2-yl]methanol

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

Procedure: A mixture of phenol (9.4 g), NaOH (1.33 g) and water (6.6 ml) was heated on a boiling water bath until the mixture became homogeneous. (2R, 3R)-3-Phenylglycidol (5.0 g) was added in small portions over a period of 10 minutes and the mixture was heated with stirring on a boiling water bath for 1 hr. The mixture was poured into a solution of NaOH (3.99 g) in ice water (75 ml) and extracted with ether (50 ml) 2 times. The ether solution was dried over anhydrous sodium sulfate and the solvent distilled off to obtain a white solid. Recrystallization from methylene chloride gave white crystals (3.1 g) of (2R, 3S)-3-phenoxy-3-phenylpropane-1,2-diol. was heated on a boiling water bath until the mixture the mixture was heated extracted with ether (50 ml) 2 times The ether solution was dried over anhydrous sodium sulfate the solvent distilled off to obtain a white solid Recrystallization from methylene chloride

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

Procedure: A mixture of phenol (9.4 g), NaOH (1.33 g) and water (6.6 ml) was heated on a boiling water bath until the mixture became homogeneous. (2R, 3R)-3-Phenylglycidol (5.0 g) was added in small portions over a period of 10 minutes and the mixture was heated with stirring on a boiling water bath for 1 hr. The mixture was poured into a solution of NaOH (3.99 g) in ice water (75 ml) and extracted with ether (50 ml) 2 times. The ether solution was dried over anhydrous sodium sulfate and the solvent distilled off to obtain a white solid. Recrystallization from methylene chloride gave white crystals (3.1 g) of (2R, 3S)-3-phenoxy-3-phenylpropane-1,2-diol. was heated on a boiling water bath until the mixture the mixture was heated extracted with ether (50 ml) 2 times The ether solution was dried over anhydrous sodium sulfate the solvent distilled off to obtain a white solid Recrystallization from methylene chloride

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

Procedure: A mixture of phenol (9.4 g), NaOH (1.33 g) and water (6.6 ml) was heated on a boiling water bath until the mixture became homogeneous. (2R, 3R)-3-Phenylglycidol (5.0 g) was added in small portions over a period of 10 minutes and the mixture was heated with stirring on a boiling water bath for 1 hr. The mixture was poured into a solution of NaOH (3.99 g) in ice water (75 ml) and extracted with ether (50 ml) 2 times. The ether solution was dried over anhydrous sodium sulfate and the solvent distilled off to obtain a white solid. Recrystallization from methylene chloride gave white crystals (3.1 g) of (2R, 3S)-3-phenoxy-3-phenylpropane-1,2-diol. was heated on a boiling water bath until the mixture the mixture was heated extracted with ether (50 ml) 2 times The ether solution was dried over anhydrous sodium sulfate the solvent distilled off to obtain a white solid Recrystallization from methylene chloride

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

Procedure: A mixture of 5-fluoro-3-methyl-1H-indole (2.91 g, 19.5 mmol) and potassium hydride 50% dispersion in mineral oil (2.8 g, 35.1 mmol) in dichloromethane (40 mL) was stirred for 10 minutes under nitrogen at room temperature. A solution of [(2R,3R)-3-phenyloxiran-2-yl]methanol (2.0 g, 13.0 mmol) and titanium isopropoxide (4.3 mL, 14.3 mmol) in dichloromethane (10 mL) was then added and the mixture was stirred at room temperature for 12 hours. After disappearance of the epoxide, the mixture was partitioned between a 1N aqueous solution of hydrochloric acid (50 mL) and ethyl acetate (50 mL). The organic layer was separated, washed with saturated sodium bicarbonate (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Biotage chromatography (FlasH40i, silica, 60% ethyl acetate/hexane) to give (2S,3S)-3-(5-fluoro-3-methyl-1H-indol-1-yl)-3-phenylpropane-1,2-diol. MS (ESI) m/z 300. the mixture was stirred at room temperature for 12 hours After disappearance of the epoxide, the mixture was partitioned between a 1N aqueous solution of hydrochloric acid (50 mL) and ethyl acetate (50 mL) The organic layer was separated washed with saturated sodium bicarbonate (50 mL) dried over anhydrous sodium sulfate filtered concentrated in vacuo The crude product was purified via Biotage chromatography (FlasH40i, silica, 60% ethyl acetate/hexane)

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of diisopropyl D-tartrate (6 mL, 28 mmol) in methylene chloride (800 mL) at −10° C. under nitrogen was added 4A molecular sieves (15 g), titanium isopropoxide (5.9 mL, 20 mmol), and cinnamyl alcohol (27 g, 200 mmol). The mixture was allowed to age for 40 minutes at −10° C., after which time it was cooled to −20° C., and treated in a dropwise fashion with a solution of tert-butyl hydroperoxide (TBHP, ˜450 mmol) in isooctane. After 18 hours at −30 to −15° C., the reaction mixture was treated with a 30% aqueous solution of sodium hydroxide (5 mL) and diethyl ether (100 mL). The cold bath was removed and the mixture was allowed to warm to ˜10° C. Magnesium sulfate (anhydrous, 15 g) was added and the mixture was stirred for 20 minutes. After the solids settled, the solution was filtered through a pad of silica gel, and washed with ether (50 mL). The filtrate was concentrated in vacuo and toluene was added to azeotropically remove the unreacted TBHP. The residue was then purified using a silica gel column (hexane:ethyl acetate/3:1) and the purified product was crystallized from hexane/ethyl acetate to yield [(2R,3R)-3-phenyloxiran-2-yl]methanol as white crystal (18 g, 60%, 98.2% ee). MS (ESI) m/z 151. After 18 hours at −30 to −15° C. The cold bath was removed to warm to ˜10° C Magnesium sulfate (anhydrous, 15 g) was added the solution was filtered through a pad of silica gel washed with ether (50 mL) The filtrate was concentrated in vacuo and toluene was added to azeotropically remove the unreacted TBHP The residue was then purified the purified product was crystallized from hexane/ethyl acetate

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of diisopropyl D-tartrate (6 mL, 28 mmol) in methylene chloride (800 mL) at −10° C. under nitrogen was added 4A molecular sieves (15 g), titanium isopropoxide (5.9 mL, 20 mmol), and cinnamyl alcohol (27 g, 200 mmol). The mixture was allowed to age for 40 minutes at −10° C., after which time it was cooled to −20° C., and treated in a dropwise fashion with a solution of tert-butyl hydroperoxide (TBHP, ˜450 mmol) in isooctane. After 18 hours at −30 to −15° C., the reaction mixture was treated with a 30% aqueous solution of sodium hydroxide (5 mL) and diethyl ether (100 mL). The cold bath was removed and the mixture was allowed to warm to ˜10° C. Magnesium sulfate (anhydrous, 15 g) was added and the mixture was stirred for 20 minutes. After the solids settled, the solution was filtered through a pad of silica gel, and washed with ether (50 mL). The filtrate was concentrated in vacuo and toluene was added to azeotropically remove the unreacted TBHP. The residue was then purified using a silica gel column (hexane:ethyl acetate/3:1) and the purified product was crystallized from hexane/ethyl acetate to yield [(2R,3R)-3-phenyloxiran-2-yl]methanol as white crystal (18 g, 60%, 98.2% ee). MS (ESI) m/z 151. After 18 hours at −30 to −15° C. The cold bath was removed to warm to ˜10° C Magnesium sulfate (anhydrous, 15 g) was added the solution was filtered through a pad of silica gel washed with ether (50 mL) The filtrate was concentrated in vacuo and toluene was added to azeotropically remove the unreacted TBHP The residue was then purified the purified product was crystallized from hexane/ethyl acetate

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

Procedure: A mixture of 1-tert-butyl-1,3-dihydro-benzimidazol-2-one (0.66 g, 3.5 mmol) and sodium hydride (60% dispersion in mineral oil, 0.15 g, 3.8 mmol) in anhydrous dimethylformamide (4 mL) was stirred for 10 minutes under nitrogen at room temperature. A solution of [(2R,3R)-3-phenyloxiran-2-yl]methanol (EXAMPLE 117, step 4, 1.07 g, 7.1 mmol) and titanium isopropoxide (2.14 mL, 7.1 mmol) in dimethylformamide (4 mL) that was aged for 20 minutes was then added and the mixture was stirred at room temperature under nitrogen for 12 hours. After disappearance of the epoxide, the mixture was partitioned between a 1N aqueous solution of hydrochloric acid (50 mL) and ethyl acetate (50 mL). The organic layer was separated, washed with saturated sodium bicarbonate (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel column (60% ethyl acetate in hexane) to give 1-tert-butyl-3-[(1S,2S)-2,3-dihydroxy-1-phenyl-propyl]-1,3-dihydro-2H-benzimidazol-2-one as an oil. MS (ES) m/z 341.2. was then added the mixture was stirred at room temperature under nitrogen for 12 hours After disappearance of the epoxide, the mixture was partitioned between a 1N aqueous solution of hydrochloric acid (50 mL) and ethyl acetate (50 mL) The organic layer was separated washed with saturated sodium bicarbonate (50 mL) dried over anhydrous sodium sulfate filtered concentrated in vacuo The residue was purified via silica gel column (60% ethyl acetate in hexane)

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

Procedure: A mixture of 5-fluoro-3-methyl-1H-indole (2.91 g, 19.5 mmol) and potassium hydride 50% dispersion in mineral oil (2.8 g, 35.1 mmol) in dichloromethane (40 mL) was stirred for 10 minutes under nitrogen at room temperature. A solution of [(2R,3R)-3-phenyloxiran-2-yl]methanol (2.0 g, 13.0 mmol) and titanium isopropoxide (4.3 mL, 14.3 mmol) in dichloromethane (10 mL) was then added and the mixture was stirred at room temperature for 12 hours. After disappearance of the epoxide, the mixture was partitioned between a 1 N aqueous solution of hydrochloric acid (50 mL) and ethyl acetate (50 mL). The organic layer was separated, washed with saturated sodium bicarbonate (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Biotage chromatography (FlasH40i, silica, 60% ethyl acetate/hexane) to give (2S,3S)-3-(5-fluoro-3-methyl-1H-indol-1-yl)-3-phenyl propane-1,2-diol. MS (ES I) m/z 300 the mixture was stirred at room temperature for 12 hours After disappearance of the epoxide, the mixture was partitioned between a 1 N aqueous solution of hydrochloric acid (50 mL) and ethyl acetate (50 mL) The organic layer was separated washed with saturated sodium bicarbonate (50 mL) dried over anhydrous sodium sulfate filtered concentrated in vacuo The crude product was purified via Biotage chromatography (FlasH40i, silica, 60% ethyl acetate/hexane)

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of diisopropyl D-tartrate (6 mL, 28 mmol) in methylene chloride (800 mL) at −10° C. under nitrogen was added 4A molecular sieves (15 g), titanium isopropoxide (5.9 mL, 20 mmol), and cinnamyl alcohol (27 g, 200 mmol). The mixture was allowed to age for 40 minutes at −10° C., after which time it was cooled to −20° C., and treated in a dropwise fashion with a solution of tert-butyl hydroperoxide (TBHP, ˜450 mmol) in isooctane. After 18 hours at −30 to -15° C., the reaction mixture was treated with a 30% aqueous solution of sodium hydroxide (5 mL) and diethyl ether (100 mL). The cold bath was removed and the mixture was allowed to warm to ˜10° C. Magnesium sulfate (anhydrous, 15 g) was added and the mixture was stirred for 20 minutes. After the solids settled, the solution was filtered through a pad of silica gel, and washed with ether (50 mL). The filtrate was concentrated in vacuo and toluene was added to azeotropically remove the unreacted TBHP. The residue was then purified using a silica gel column (hexane:ethyl acetate/3:1) and the purified product was crystallized from hexane/ethyl acetate to yield [(2R,3R)-3-phenyloxiran-2-yl]methanol as white crystal (18 g, 60%, 98.2% ee). MS (ESI) m/z 151. After 18 hours at −30 to -15° C. The cold bath was removed to warm to ˜10° C Magnesium sulfate (anhydrous, 15 g) was added the solution was filtered through a pad of silica gel washed with ether (50 mL) The filtrate was concentrated in vacuo and toluene was added to azeotropically remove the unreacted TBHP The residue was then purified the purified product was crystallized from hexane/ethyl acetate

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

Procedure: A mixture of 5-fluoro-3-methyl-1H-indole (2.91 g, 19.5 mmol) and potassium hydride 50% dispersion in mineral oil (2.8 g, 35.1 mmol) in dichloromethane (40 mL) was stirred for 10 minutes under nitrogen at room temperature. A solution of [(2R,3R)-3-phenyloxiran-2-yl]methanol (2.0 g, 13.0 mmol) and titanium isopropoxide (4.3 mL, 14.3 mmol) in dichloromethane (10 mL) was then added and the mixture was stirred at room temperature for 12 hours. After disappearance of the epoxide, the mixture was partitioned between a 1N aqueous solution of hydrochloric acid (50 mL) and ethyl acetate (50 mL). The organic layer was separated, washed with saturated sodium bicarbonate (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Biotage chromatography (FlasH40i, silica, 60% ethyl acetate/hexane) to give (2S,3S)-3-(5-fluoro-3-methyl-1H-indol-1-yl)-3-phenylpropane-1,2-diol. MS (ESI) m/z 300 the mixture was stirred at room temperature for 12 hours After disappearance of the epoxide, the mixture was partitioned between a 1N aqueous solution of hydrochloric acid (50 mL) and ethyl acetate (50 mL) The organic layer was separated washed with saturated sodium bicarbonate (50 mL) dried over anhydrous sodium sulfate filtered concentrated in vacuo The crude product was purified via Biotage chromatography (FlasH40i, silica, 60% ethyl acetate/hexane)

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of diisopropyl D-tartrate (6 mL, 28 mmol) in methylene chloride (800 mL) at −10° C. under nitrogen was added 4A molecular sieves (15 g), titanium isopropoxide (5.9 mL, 20 mmol), and cinnamyl alcohol (27 g, 200 mmol). The mixture was allowed to age for 40 minutes at −10° C., after which time it was cooled to −20° C., and treated in a dropwise fashion with a solution of tert-butyl hydroperoxide (TBHP, ˜450 mmol) in isooctane. After 18 hours at −30 to −15° C., the reaction mixture was treated with a 30% aqueous solution of sodium hydroxide (5 mL) and diethyl ether (100 mL). The cold bath was removed and the mixture was allowed to warm to ˜10° C. Magnesium sulfate (anhydrous, 15 g) was added and the mixture was stirred for 20 minutes. After the solids settled, the solution was filtered through a pad of silica gel, and washed with ether (50 mL). The filtrate was concentrated in vacuo and toluene was added to azeotropically remove the unreacted TBHP. The residue was then purified using a silica gel column (hexane:ethyl acetate/3:1) and the purified product was crystallized from hexane/ethyl acetate to yield [(2R,3R)-3-phenyloxiran-2-yl]methanol as white crystal (18 g, 60%, 98.2% ee). MS (ESI) m/z 151. After 18 hours at −30 to −15° C. The cold bath was removed to warm to ˜10° C Magnesium sulfate (anhydrous, 15 g) was added the solution was filtered through a pad of silica gel washed with ether (50 mL) The filtrate was concentrated in vacuo and toluene was added to azeotropically remove the unreacted TBHP The residue was then purified the purified product was crystallized from hexane/ethyl acetate

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

Procedure: A mixture of phenol (9.4 g), NaOH (1.33 g) and water (6.6 ml) was heated on a boiling water bath until the mixture became homogeneous. (2R, 3R)-3-Phenylglycidol (5.0 g) was added in small portions over a period of 10 minutes and the mixture was heated with stirring on a boiling water bath for 1 hr. The mixture was poured into a solution of NaOH (3.99 g) in ice water (75 ml) and extracted with ether (50 ml) 2 times. The ether solution was dried over anhydrous sodium sulfate and the solvent distilled off to obtain a white solid. Recrystallization from methylene chloride gave white crystals (3.1 g) of (2R, 3S)-3-phenoxy-3-phenylpropane-1,2-diol. was heated on a boiling water bath until the mixture the mixture was heated extracted with ether (50 ml) 2 times The ether solution was dried over anhydrous sodium sulfate the solvent distilled off to obtain a white solid Recrystallization from methylene chloride