(5S)-5-(2-methylpropyl)morpholin-3-one

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

Procedure: To an ice cold, stirred suspension of NaH (60% in oil, 1.6 g, 39.0 mmol) in toluene (53 mL) was added dropwise a solution of (S)-2-amino-4-methylpentan-1-ol (2.0 g, 17.0 mmol) in toluene (37 mL). After the addition was completed, the reaction mixture was warmed to room temperature and a solution of ethyl chloroacetate (2.3 g, 19.0 mmol) in toluene (10 mL) was added in a dropwise manner. The resulting mixture was then stirred at reflux for 20 h, cooled to room temperature, and solid ammonium chloride (2.1 g, 39.0 mmol) was added to the reaction. The mixture was stirred for 20 min and then concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 98:2 CH2Cl2/CH3OH to 95:5 CH2Cl2/CH3OH) to give (S)-5-iso-butylmorpholin-3-one (1.9 g, 70%) as a light yellow oil. To ice-cold THF (8 mL) was added lithium aluminum hydride (1.0 M solution in THF, 23.0 mL, 23.0 mmol). Once the addition was complete, a solution of (S)-5-iso-butylmorpholin-3-one (1.8 g, 12.0 mmol) in THF (7.0 mL) was added dropwise over 20 min. Once the addition was completed, the ice bath was removed and the reaction mixture stirred at reflux for 20 h. The reaction was cooled in an ice-bath and to this was slowly added H2O (1.2 mL), then 15% aqueous solution of sodium hydroxide (1.2 mL), and then H2O (1.2 mL). The resulting mixture was stirred at room temperature for 1.5 h and then filtered washing the solids with EtOAc (50 mL). The filtrate was concentrated at room temperature under reduced pressure to provide (S)-3-iso-butylmorpholine (1.6 g, 95%) as a light yellow oil. 1H NMR and MS consistent. Once the addition Once the addition the ice bath was removed at reflux for 20 h The reaction was cooled in an ice-bath The resulting mixture was stirred at room temperature for 1.5 h filtered washing the solids with EtOAc (50 mL) The filtrate was concentrated at room temperature under reduced pressure

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

Procedure: To an ice cold, stirred suspension of NaH (60% in oil, 1.6 g, 39.0 mmol) in toluene (53 mL) was added dropwise a solution of (S)-2-amino-4-methylpentan-1-ol (2.0 g, 17.0 mmol) in toluene (37 mL). After the addition was completed, the reaction mixture was warmed to room temperature and a solution of ethyl chloroacetate (2.3 g, 19.0 mmol) in toluene (10 mL) was added in a dropwise manner. The resulting mixture was then stirred at reflux for 20 h, cooled to room temperature, and solid ammonium chloride (2.1 g, 39.0 mmol) was added to the reaction. The mixture was stirred for 20 min and then concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 98:2 CH2Cl2/CH3OH to 95:5 CH2Cl2/CH3OH) to give (S)-5-iso-butylmorpholin-3-one (1.9 g, 70%) as a light yellow oil. To ice-cold THF (8 mL) was added lithium aluminum hydride (1.0 M solution in THF, 23.0 mL, 23.0 mmol). Once the addition was complete, a solution of (S)-5-iso-butylmorpholin-3-one (1.8 g, 12.0 mmol) in THF (7.0 mL) was added dropwise over 20 min. Once the addition was completed, the ice bath was removed and the reaction mixture stirred at reflux for 20 h. The reaction was cooled in an ice-bath and to this was slowly added H2O (1.2 mL), then 15% aqueous solution of sodium hydroxide (1.2 mL), and then H2O (1.2 mL). The resulting mixture was stirred at room temperature for 1.5 h and then filtered washing the solids with EtOAc (50 mL). The filtrate was concentrated at room temperature under reduced pressure to provide (S)-3-iso-butylmorpholine (1.6 g, 95%) as a light yellow oil. 1H NMR and MS consistent. Once the addition Once the addition the ice bath was removed at reflux for 20 h The reaction was cooled in an ice-bath The resulting mixture was stirred at room temperature for 1.5 h filtered washing the solids with EtOAc (50 mL) The filtrate was concentrated at room temperature under reduced pressure

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

Procedure: To an ice cold, stirred suspension of NaH (60% in oil, 1.6 g, 39.0 mmol) in toluene (53 mL) was added dropwise a solution of (S)-2-amino-4-methylpentan-1-ol (2.0 g, 17.0 mmol) in toluene (37 mL). After the addition was completed, the reaction mixture was warmed to room temperature and a solution of ethyl chloroacetate (2.3 g, 19.0 mmol) in toluene (10 mL) was added in a dropwise manner. The resulting mixture was then stirred at reflux for 20 h, cooled to room temperature, and solid ammonium chloride (2.1 g, 39.0 mmol) was added to the reaction. The mixture was stirred for 20 min and then concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 98:2 CH2Cl2/CH3OH to 95:5 CH2Cl2/CH3OH) to give (S)-5-iso-butylmorpholin-3-one (1.9 g, 70%) as a light yellow oil. To ice-cold THF (8 mL) was added lithium aluminum hydride (1.0 M solution in THF, 23.0 mL, 23.0 mmol). Once the addition was complete, a solution of (S)-5-iso-butylmorpholin-3-one (1.8 g, 12.0 mmol) in THF (7.0 mL) was added dropwise over 20 min. Once the addition was completed, the ice bath was removed and the reaction mixture stirred at reflux for 20 h. The reaction was cooled in an ice-bath and to this was slowly added H2O (1.2 mL), then 15% aqueous solution of sodium hydroxide (1.2 mL), and then H2O (1.2 mL). The resulting mixture was stirred at room temperature for 1.5 h and then filtered washing the solids with EtOAc (50 mL). The filtrate was concentrated at room temperature under reduced pressure to provide (S)-3-iso-butylmorpholine (1.6 g, 95%) as a light yellow oil. 1H NMR and MS consistent. After the addition at reflux for 20 h cooled to room temperature The mixture was stirred for 20 min concentrated under reduced pressure The crude material was purified by column chromatography (silica gel, 98:2 CH2Cl2/CH3OH to 95:5 CH2Cl2/CH3OH)

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

Procedure: To an ice cold, stirred suspension of NaH (60% in oil, 1.6 g, 39.0 mmol) in toluene (53 mL) was added dropwise a solution of (S)-2-amino-4-methylpentan-1-ol (2.0 g, 17.0 mmol) in toluene (37 mL). After the addition was completed, the reaction mixture was warmed to room temperature and a solution of ethyl chloroacetate (2.3 g, 19.0 mmol) in toluene (10 mL) was added in a dropwise manner. The resulting mixture was then stirred at reflux for 20 h, cooled to room temperature, and solid ammonium chloride (2.1 g, 39.0 mmol) was added to the reaction. The mixture was stirred for 20 min and then concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 98:2 CH2Cl2/CH3OH to 95:5 CH2Cl2/CH3OH) to give (S)-5-iso-butylmorpholin-3-one (1.9 g, 70%) as a light yellow oil. To ice-cold THF (8 mL) was added lithium aluminum hydride (1.0 M solution in THF, 23.0 mL, 23.0 mmol). Once the addition was complete, a solution of (S)-5-iso-butylmorpholin-3-one (1.8 g, 12.0 mmol) in THF (7.0 mL) was added dropwise over 20 min. Once the addition was completed, the ice bath was removed and the reaction mixture stirred at reflux for 20 h. The reaction was cooled in an ice-bath and to this was slowly added H2O (1.2 mL), then 15% aqueous solution of sodium hydroxide (1.2 mL), and then H2O (1.2 mL). The resulting mixture was stirred at room temperature for 1.5 h and then filtered washing the solids with EtOAc (50 mL). The filtrate was concentrated at room temperature under reduced pressure to provide (S)-3-iso-butylmorpholine (1.6 g, 95%) as a light yellow oil. 1H NMR and MS consistent. After the addition at reflux for 20 h cooled to room temperature The mixture was stirred for 20 min concentrated under reduced pressure The crude material was purified by column chromatography (silica gel, 98:2 CH2Cl2/CH3OH to 95:5 CH2Cl2/CH3OH)

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

Procedure: To an ice cold, stirred suspension of NaH (60% in oil, 1.6 g, 39.0 mmol) in toluene (53 mL) was added dropwise a solution of (S)-2-amino-4-methylpentan-1-ol (2.0 g, 17.0 mmol) in toluene (37 mL). After the addition was completed, the reaction mixture was warmed to room temperature and a solution of ethyl chloroacetate (2.3 g, 19.0 mmol) in toluene (10 mL) was added in a dropwise manner. The resulting mixture was then stirred at reflux for 20 h, cooled to room temperature, and solid ammonium chloride (2.1 g, 39.0 mmol) was added to the reaction. The mixture was stirred for 20 min and then concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 98:2 CH2Cl2/CH3OH to 95:5 CH2Cl2/CH3OH) to give (S)-5-iso-butylmorpholin-3-one (1.9 g, 70%) as a light yellow oil. To ice-cold THF (8 mL) was added lithium aluminum hydride (1.0 M solution in THF, 23.0 mL, 23.0 mmol). Once the addition was complete, a solution of (S)-5-iso-butylmorpholin-3-one (1.8 g, 12.0 mmol) in THF (7.0 mL) was added dropwise over 20 min. Once the addition was completed, the ice bath was removed and the reaction mixture stirred at reflux for 20 h. The reaction was cooled in an ice-bath and to this was slowly added H2O (1.2 mL), then 15% aqueous solution of sodium hydroxide (1.2 mL), and then H2O (1.2 mL). The resulting mixture was stirred at room temperature for 1.5 h and then filtered washing the solids with EtOAc (50 mL). The filtrate was concentrated at room temperature under reduced pressure to provide (S)-3-iso-butylmorpholine (1.6 g, 95%) as a light yellow oil. 1H NMR and MS consistent. Once the addition Once the addition the ice bath was removed at reflux for 20 h The reaction was cooled in an ice-bath The resulting mixture was stirred at room temperature for 1.5 h filtered washing the solids with EtOAc (50 mL) The filtrate was concentrated at room temperature under reduced pressure

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

Procedure: To an ice cold, stirred suspension of NaH (60% in oil, 1.6 g, 39.0 mmol) in toluene (53 mL) was added dropwise a solution of (S)-2-amino-4-methylpentan-1-ol (2.0 g, 17.0 mmol) in toluene (37 mL). After the addition was completed, the reaction mixture was warmed to room temperature and a solution of ethyl chloroacetate (2.3 g, 19.0 mmol) in toluene (10 mL) was added in a dropwise manner. The resulting mixture was then stirred at reflux for 20 h, cooled to room temperature, and solid ammonium chloride (2.1 g, 39.0 mmol) was added to the reaction. The mixture was stirred for 20 min and then concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 98:2 CH2Cl2/CH3OH to 95:5 CH2Cl2/CH3OH) to give (S)-5-iso-butylmorpholin-3-one (1.9 g, 70%) as a light yellow oil. To ice-cold THF (8 mL) was added lithium aluminum hydride (1.0 M solution in THF, 23.0 mL, 23.0 mmol). Once the addition was complete, a solution of (S)-5-iso-butylmorpholin-3-one (1.8 g, 12.0 mmol) in THF (7.0 mL) was added dropwise over 20 min. Once the addition was completed, the ice bath was removed and the reaction mixture stirred at reflux for 20 h. The reaction was cooled in an ice-bath and to this was slowly added H2O (1.2 mL), then 15% aqueous solution of sodium hydroxide (1.2 mL), and then H2O (1.2 mL). The resulting mixture was stirred at room temperature for 1.5 h and then filtered washing the solids with EtOAc (50 mL). The filtrate was concentrated at room temperature under reduced pressure to provide (S)-3-iso-butylmorpholine (1.6 g, 95%) as a light yellow oil. 1H NMR and MS consistent. After the addition at reflux for 20 h cooled to room temperature The mixture was stirred for 20 min concentrated under reduced pressure The crude material was purified by column chromatography (silica gel, 98:2 CH2Cl2/CH3OH to 95:5 CH2Cl2/CH3OH)

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

Procedure: (S)-5-(2-Methylpropyl)-3-morpholinone, 3 g (0.019 mol), is suspended in a solution of 50 ml of concentrated hydrochloric acid and 50 ml of water, refluxed for four hours, cooled to room temperature, and extracted with 200 ml of dichloromethane. The aqueous layer is separated, evaporated in vacuo, the residue dissolved in 200 ml of water and the pH adjusted with a 10% aqueous solution of sodium hydroxide to pH 10-10.5. The solution is cooled to 5° C. and 3.73 g (0.022 mol) of benzylchloroformate is added dropwise while the pH is maintained at pH 10 with a 10% aqueous solution of sodium hydroxide. The mixture is stirred one hour, extracted with 100 ml of diethylether, the aqueous layer is separated and the pH is adjusted to pH 3-4 by the addition of a 10% aqueous solution of hydrochloric acid. The mixture is extracted with dichloromethane, 3×200 ml. The dichloromethane layer is separated, washed with a saturated aqueous solution of sodium chloride, 3×200 ml, separated, dried over sodium sulfate, evaporated and the residue is purified by chromatography using silica gel and eluting with dichloromethane-methanol (95:5) to give (S)-[[4-methyl2[[(phenylmethoxy)carbonyl]amino]pentyl]oxy]acetic acid, 5 g; [α]D25 -30.5 (c 0.55, methanol). refluxed for four hours extracted with 200 ml of dichloromethane The aqueous layer is separated evaporated in vacuo the residue dissolved in 200 ml of water The solution is cooled to 5° C. extracted with 100 ml of diethylether the aqueous layer is separated the pH is adjusted to pH 3-4 by the addition of a 10% aqueous solution of hydrochloric acid The mixture is extracted with dichloromethane, 3×200 ml The dichloromethane layer is separated washed with a saturated aqueous solution of sodium chloride, 3×200 ml separated dried over sodium sulfate evaporated the residue is purified by chromatography eluting with dichloromethane-methanol (95:5)

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

Procedure: (S)-2-Chloro-N-[1-(hydroxymethyl)-3-methylbutyl]acetamide, 26.34 g (0.136 mol), is dissolved in 450 ml of tetrahydrofuran, the solution is cooled to 0°-5° C. and 7.8 g (0.195 mol) of 60% sodium hydride in mineral oil dispersion is slowly added. The mixture is allowed to reach room temperature and is stirred for 14 hours. Water, 10 ml, is added, the solvents evaporated in vacuo and the residue suspended in 250 ml of chloroform and washed with 100 ml of water and then a saturated aqueous solution of sodium chloride, 2×200 ml. The chloroform layer is separated, dried over sodium sulfate, and evaporated in vacuo. The residue is purified by chromatography using silica gel and eluting with dichloromethane methanol (95:5) to give (S)-5-(2-methylpropyl)-3-morpholinone, 5.1 g, mp 69°-70°; [α]D25 -13.7° (c 1.11, methanol). the solution is cooled to 0°-5° C. to reach room temperature the solvents evaporated in vacuo washed with 100 ml of water The chloroform layer is separated dried over sodium sulfate evaporated in vacuo The residue is purified by chromatography eluting with dichloromethane methanol (95:5)

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

Procedure: To an ice cold, stirred suspension of NaH (60% in oil, 1.6 g, 39.0 mmol) in toluene (53 mL) was added dropwise a solution of (S)-2-amino-4-methylpentan-1-ol (2.0 g, 17.0 mmol) in toluene (37 mL). After the addition was completed, the reaction mixture was warmed to room temperature and a solution of ethyl chloroacetate (2.3 g, 19.0 mmol) in toluene (10 mL) was added in a dropwise manner. The resulting mixture was then stirred at reflux for 20 h, cooled to room temperature, and solid ammonium chloride (2.1 g, 39.0 mmol) was added to the reaction. The mixture was stirred for 20 min and then concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 98:2 CH2Cl2/CH3OH to 95:5 CH2Cl2/CH3OH) to give (S)-5-iso-butylmorpholin-3-one (1.9 g, 70%) as a light yellow oil. To ice-cold THF (8 mL) was added lithium aluminum hydride (1.0 M solution in THF, 23.0 mL, 23.0 mmol). Once the addition was complete, a solution of (S)-5-iso-butylmorpholin-3-one (1.8 g, 12.0 mmol) in THF (7.0 mL) was added dropwise over 20 min. Once the addition was completed, the ice bath was removed and the reaction mixture stirred at reflux for 20 h. The reaction was cooled in an ice-bath and to this was slowly added H2O (1.2 mL), then 15% aqueous solution of sodium hydroxide (1.2 mL), and then H2O (1.2 mL). The resulting mixture was stirred at room temperature for 1.5 h and then filtered washing the solids with EtOAc (50 mL). The filtrate was concentrated at room temperature under reduced pressure to provide (S)-3-iso-butylmorpholine (1.6 g, 95%) as a light yellow oil. 1H NMR and MS consistent. Once the addition Once the addition the ice bath was removed at reflux for 20 h The reaction was cooled in an ice-bath The resulting mixture was stirred at room temperature for 1.5 h filtered washing the solids with EtOAc (50 mL) The filtrate was concentrated at room temperature under reduced pressure

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

Procedure: To an ice cold, stirred suspension of NaH (60% in oil, 1.6 g, 39.0 mmol) in toluene (53 mL) was added dropwise a solution of (S)-2-amino-4-methylpentan-1-ol (2.0 g, 17.0 mmol) in toluene (37 mL). After the addition was completed, the reaction mixture was warmed to room temperature and a solution of ethyl chloroacetate (2.3 g, 19.0 mmol) in toluene (10 mL) was added in a dropwise manner. The resulting mixture was then stirred at reflux for 20 h, cooled to room temperature, and solid ammonium chloride (2.1 g, 39.0 mmol) was added to the reaction. The mixture was stirred for 20 min and then concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 98:2 CH2Cl2/CH3OH to 95:5 CH2Cl2/CH3OH) to give (S)-5-iso-butylmorpholin-3-one (1.9 g, 70%) as a light yellow oil. To ice-cold THF (8 mL) was added lithium aluminum hydride (1.0 M solution in THF, 23.0 mL, 23.0 mmol). Once the addition was complete, a solution of (S)-5-iso-butylmorpholin-3-one (1.8 g, 12.0 mmol) in THF (7.0 mL) was added dropwise over 20 min. Once the addition was completed, the ice bath was removed and the reaction mixture stirred at reflux for 20 h. The reaction was cooled in an ice-bath and to this was slowly added H2O (1.2 mL), then 15% aqueous solution of sodium hydroxide (1.2 mL), and then H2O (1.2 mL). The resulting mixture was stirred at room temperature for 1.5 h and then filtered washing the solids with EtOAc (50 mL). The filtrate was concentrated at room temperature under reduced pressure to provide (S)-3-iso-butylmorpholine (1.6 g, 95%) as a light yellow oil. 1H NMR and MS consistent. After the addition at reflux for 20 h cooled to room temperature The mixture was stirred for 20 min concentrated under reduced pressure The crude material was purified by column chromatography (silica gel, 98:2 CH2Cl2/CH3OH to 95:5 CH2Cl2/CH3OH)