tert-butyl N-[(2S,3S)-1-hydroxy-3-methylpentan-2-yl]carbamate

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

Procedure: To a solution of pyridine--sulfur trioxide complex (5.1 g, 32 mmol) in dimethyl sulfoxide (20 ml)--dichloromethane (20 ml) was added dropwise a solution of (S)-N-(tert-butoxycarbonyl)-isoleucinol (1.4 g, 6.5 mmol) and triethylamine (3.2 g, 32 mmol) in dimethyl sulfoxide (20 ml)--dichloromethane (20 ml) under an argon gas stream and ice-cooling. After stirring for 30 minutes, the reaction solution was poured into water, and extracted with dichloromethane. The organic layer was washed with a saturated aqueous citric acid solution, an aqueous sodium bicarbonate solution, water and an aqueous sodium chloride solution, successively. After drying over sodium sulfate, the solvent was evaporated under reduced pressure to give (2S,3S)-2-(tert-butoxycarbonylamino)-3-methylpentanal (1.3 g). extracted with dichloromethane The organic layer was washed with a saturated aqueous citric acid solution After drying over sodium sulfate the solvent was evaporated under reduced pressure

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

Procedure: This compound was prepared in 97% yield from the ester 4c (9.84 g, 40 mmol) by reduction with lithium borohydride in dry DME analogous to the method described earlier1,2. TLC Rf 0.47 (eluent MeOH/CHCl3, 7/93). 1H NMR (CDCl3) δ 0.83-1.03 (m, 6H, CHCH3, CH2CH3), 1.03-1.40 (m, 2H, CH2CH3, CH2CH3), 1.44 (s, 9H, t-Bu), 2.21-2.61 (m, 1H, CHCH3), 3.32-3.88 (m, 4H, CHCH2OH), 4.52-4.68 (m, 1H, NH), CI MS, m/e 218 (M+ +1).

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

Procedure: This compound was prepared in 97% yield from the ester 4c (9.84 g, 40 mmol) by reduction with lithium borohydride in dry DME analogous to the method described earlier1,2. TLC Rf 0.47 (eluent MeOH/CHCl3, 7/93). 1H NMR (CDCl3) δ 0.83-1.03 (m, 6H, CHCH3, CH2CH3), 1.03-1.40 (m, 2H, CH2CH3, CH2CH3), 1.44 (s, 9H, t-Bu), 2.21-2.61 (m, 1H, CHCH3), 3.32-3.88 (m, 4H, CHCH2OH), 4.52-4.68 (m, 1H, NH), CI MS, m/e 218 (M+ +1).

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

Procedure: In 5 ml of 1,2-dimethoxyethane (DME), 1.201 g of Boc-Ile-OH.1/2H2O was dissolved and 550 μl of N-methylmorpholine and 650 μl of isobutyl chloroformate were successively added dropwise at −15° C. After stirring for 1 min, the formed N-methylmorpholine hydrochloride was filtered off and washed twice with 2.5 ml each of DME. The filtrate and washings were combined and 284 mg of sodium borohydride in 2.5 ml of water was added in one portion. After 30 sec, 125 ml of water was added and the mixture was extracted with 25 ml of ethyl acetate and dried over anhydrous sodium sulfate. The dried solution was evaporated under reduced pressure to give 1.040 g of the title compound. 1/2H2O was dissolved the formed N-methylmorpholine hydrochloride was filtered off washed twice with 2.5 ml each of DME 284 mg of sodium borohydride in 2.5 ml of water was added in one portion After 30 sec 125 ml of water was added the mixture was extracted with 25 ml of ethyl acetate dried over anhydrous sodium sulfate The dried solution was evaporated under reduced pressure

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

Procedure: In 5 ml of 1,2-dimethoxyethane (DME), 1.201 g of Boc-Ile-OH.1/2H2O was dissolved and 550 μl of N-methylmorpholine and 650 μl of isobutyl chloroformate were successively added dropwise at −15° C. After stirring for 1 min, the formed N-methylmorpholine hydrochloride was filtered off and washed twice with 2.5 ml each of DME. The filtrate and washings were combined and 284 mg of sodium borohydride in 2.5 ml of water was added in one portion. After 30 sec, 125 ml of water was added and the mixture was extracted with 25 ml of ethyl acetate and dried over anhydrous sodium sulfate. The dried solution was evaporated under reduced pressure to give 1.040 g of the title compound. 1/2H2O was dissolved the formed N-methylmorpholine hydrochloride was filtered off washed twice with 2.5 ml each of DME 284 mg of sodium borohydride in 2.5 ml of water was added in one portion After 30 sec 125 ml of water was added the mixture was extracted with 25 ml of ethyl acetate dried over anhydrous sodium sulfate The dried solution was evaporated under reduced pressure

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

Procedure: This compound was prepared in 97% yield from the ester 4c (9.84 g, 40 mmol) by reduction with lithium borohydride in dry DME analogous to the method described earlier1,2. TLC Rf 0.47 (eluent MeOH/CHCl3, 7/93). 1H NMR (CDCl3) δ 0.83-1.03 (m, 6H, CHCH3, CH2CH3), 1.03-1.40 (m, 2H, CH2CH3, CH2CH3), 1.44 (s, 9H, t-Bu), 2.21-2.61 (m, 1H, CHCH3), 3.32-3.88 (m, 4H, CHCH2OH), 4.52-4.68 (m, 1H, NH), CI MS, m/e 218 (M+ +1).

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

Procedure: In 5 ml of 1,2-dimethoxyethane (DME), 1.201 g of Boc-Ile-OH.1/2H2O was dissolved and 550 μl of N-methylmorpholine and 650 μl of isobutyl chloroformate were successively added dropwise at −15° C. After stirring for 1 min, the formed N-methylmorpholine hydrochloride was filtered off and washed twice with 2.5 ml each of DME. The filtrate and washings were combined and 284 mg of sodium borohydride in 2.5 ml of water was added in one portion. After 30 sec, 125 ml of water was added and the mixture was extracted with 25 ml of ethyl acetate and dried over anhydrous sodium sulfate. The dried solution was evaporated under reduced pressure to give 1.040 g of the title compound. 1/2H2O was dissolved the formed N-methylmorpholine hydrochloride was filtered off washed twice with 2.5 ml each of DME 284 mg of sodium borohydride in 2.5 ml of water was added in one portion After 30 sec 125 ml of water was added the mixture was extracted with 25 ml of ethyl acetate dried over anhydrous sodium sulfate The dried solution was evaporated under reduced pressure

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

Procedure: In 5 ml of 1,2-dimethoxyethane (DME), 1.201 g of Boc-Ile-OH.1/2H2O was dissolved and 550 μl of N-methylmorpholine and 650 μl of isobutyl chloroformate were successively added dropwise at −15° C. After stirring for 1 min, the formed N-methylmorpholine hydrochloride was filtered off and washed twice with 2.5 ml each of DME. The filtrate and washings were combined and 284 mg of sodium borohydride in 2.5 ml of water was added in one portion. After 30 sec, 125 ml of water was added and the mixture was extracted with 25 ml of ethyl acetate and dried over anhydrous sodium sulfate. The dried solution was evaporated under reduced pressure to give 1.040 g of the title compound. 1/2H2O was dissolved the formed N-methylmorpholine hydrochloride was filtered off washed twice with 2.5 ml each of DME 284 mg of sodium borohydride in 2.5 ml of water was added in one portion After 30 sec 125 ml of water was added the mixture was extracted with 25 ml of ethyl acetate dried over anhydrous sodium sulfate The dried solution was evaporated under reduced pressure

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

Procedure: To a suspension of N-Boc-L-isoleucinol (5 g, 23 mmol) in dichloromethane (250 mL) and DMSO (50 mL) at 0° C. was added TEA (10 mL, 73 mmol) followed by slow addition of the solution of sulfur trioxide pyridine complex (11 mL, 69 mmol) in DMSO (50 mL) via syringe. The reaction mixture was concentrated and was diluted with ether (200 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×200 mL), which was then washed with brine (150 mL), water (150 mL) and NaHCO3 (150 mL) sequentially. The organic layers were dried over MgSO4, filtered and concentrated. The residue was dried on pump to afford ((1S,2S)-1-formyl-2-methyl-butyl)-carbamic acid tert-butyl ester (4.47 g, 90% yield) as light-yellow clear liquid. The reaction mixture was concentrated was diluted with ether (200 mL) The layers were separated the aqueous layer was extracted with ethyl acetate (3×200 mL), which was then washed with brine (150 mL), water (150 mL) and NaHCO3 (150 mL) sequentially The organic layers were dried over MgSO4 filtered concentrated The residue was dried on pump

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

Procedure: To an ice cold solution of Boc-isoleucinol (3.89 g, 17.9 mmol) in DMSO (15 mL) and DCM (200 mL) was added DIEA (9.7 mL, 55.5 mmol), followed by dropwise addition of a solution of Py.SO3 (8.83 g, 55.5 mmol) in DMSO (50 mL, +10 mL to rinse the funnel). The reaction mixture was stirred at rt for 2 h. After removal of the DCM, the residue was diluted with Et2O (400 mL) and washed with H2O (2×100 mL) and brine (150 mL). The aqueous layer was back extracted with Et2O (100 mL). The combined Et2O layer was washed with saturated NaHCO3 (150 mL) and dried (Na2SO4). The solvent was removed to give the titled compound (3.97 g). to rinse the funnel) After removal of the DCM the residue was diluted with Et2O (400 mL) washed with H2O (2×100 mL) and brine (150 mL) The aqueous layer was back extracted with Et2O (100 mL) The combined Et2O layer was washed with saturated NaHCO3 (150 mL) dried (Na2SO4) The solvent was removed

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

Procedure: 9.59 ml (69.0 mmole) of triethylamine and 11.0 g (69.0 mmole) of a pyridine/sulfur trioxide complex were added to a solution of 5.0 g (23.0 mmole) of N-(t-butoxycarbonyl)-L-isoleucinol in 50 ml of dimethyl sulfoxide, and the mixture was stirred at room temperature for 15 minutes. At the end of this time, the reaction mixture was poured onto ice-water, and extracted with diethyl ether. The organic extract was washed with a 5% w/v aqueous solution of citric acid, with a 5% w/v aqueous solution of sodium bicarbonate and with water, in that order. It was then dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, to give 5.0 g of N-(t-butoxycarbonyl)-L-leucinal as an oily substance. At the end of this time, the reaction mixture was poured onto ice-water extracted with diethyl ether The organic extract was washed with a 5% w/v aqueous solution of citric acid, with a 5% w/v aqueous solution of sodium bicarbonate and with water, in that order It was then dried over anhydrous sodium sulfate The solvent was then removed by distillation under reduced pressure

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

Procedure: To a solution of pyridine--sulfur trioxide complex (5.1 g, 32 mmol) in dimethyl sulfoxide (20 ml)--dichloromethane (20 ml) was added dropwise a solution of (S)-N-(tert-butoxycarbonyl)-isoleucinol (1.4 g, 6.5 mmol) and triethylamine (3.2 g, 32 mmol) in dimethyl sulfoxide (20 ml)--dichloromethane (20 ml) under an argon gas stream and ice-cooling. After stirring for 30 minutes, the reaction solution was poured into water, and extracted with dichloromethane. The organic layer was washed with a saturated aqueous citric acid solution, an aqueous sodium bicarbonate solution, water and an aqueous sodium chloride solution, successively. After drying over sodium sulfate, the solvent was evaporated under reduced pressure to give (2S,3S)-2-(tert-butoxycarbonylamino)-3-methylpentanal (1.3 g). extracted with dichloromethane The organic layer was washed with a saturated aqueous citric acid solution After drying over sodium sulfate the solvent was evaporated under reduced pressure