tert-butyl N-[(2S,3S)-3-methyl-1-oxopentan-2-yl]carbamate

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

Procedure: Glycine methyl ester hydrochloride (4.41 g, 0.035 mol) was dissolved in 1,2-dichloroethane (50 mL) and DMF (5 mL) and treated with 3A molecular sieves (10 g) and N-t-butoxycarbonyl-isoleucinal (6.3 g, 0.029 mol) with stirring at 0° C. Sodium triacetoxyborohydride (9.27 g, 0.044 mol) was added, and the pH of the mixture was adjusted to 6 with triethylamine (3 mL, 0.022 mol). After stirring for 18 h the mixture was filtered, concentrated to a small volume and partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic phase was washed with aqueous saturated NaHCO3 solution, brine, and dried (Na2SO4). Filtration and concentration afforded a residue which was purified by flash chromatography (SiO2, EtOAc:hexane, 1:3) to give (6). After stirring for 18 h the mixture was filtered concentrated to a small volume partitioned between EtOAc and water The aqueous layer was extracted with EtOAc (2×50 mL) The combined organic phase was washed with aqueous saturated NaHCO3 solution, brine dried (Na2SO4) Filtration and concentration afforded a residue which was purified by flash chromatography (SiO2, EtOAc:hexane, 1:3)

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

Procedure: Glycine methyl ester hydrochloride (4.41 g, 0.035 mol) was dissolved in 1,2-dichloroethane (50 mL) and DMF (5 mL) and treated with 3A molecular sieves (10 g) and N-t-butoxycarbonyl-isoleucinal (6.3 g, 0.029 mol) with stirring at 0° C. Sodium triacetoxyborohydride (9.27 g, 0.044 mol) was added, and the pH of the mixture was adjusted to 6 with triethylamine (3 mL, 0.022 mol). After stirring for 18 h the mixture was filtered, concentrated to a small volume and partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic phase was washed with aqueous saturated NaHCO3 solution, brine, and dried (Na2SO4). Filtration and concentration afforded a residue which was purified by flash chromatography (SiO2, EtOAc:hexane, 1:3) to give (6). After stirring for 18 h the mixture was filtered concentrated to a small volume partitioned between EtOAc and water The aqueous layer was extracted with EtOAc (2×50 mL) The combined organic phase was washed with aqueous saturated NaHCO3 solution, brine dried (Na2SO4) Filtration and concentration afforded a residue which was purified by flash chromatography (SiO2, EtOAc:hexane, 1:3)

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

Procedure: Glycine methyl ester hydrochloride (4.41 g, 0.035 mol) was dissolved in 1,2-dichloroethane (50 mL) and DMF (5 mL) and treated with 3A molecular sieves (10 g) and N-t-butoxycarbonyl-isoleucinal (6.3 g, 0.029 mol) with stirring at 0° C. Sodium triacetoxyborohydride (9.27 g, 0.044 mol) was added, and the pH of the mixture was adjusted to 6 with triethylamine (3 mL, 0.022 mol). After stirring for 18 h the mixture was filtered, concentrated to a small volume and partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic phase was washed with aqueous saturated NaHCO3 solution, brine, and dried (Na2SO4). Filtration and concentration afforded a residue which was purified by flash chromatography (SiO2, EtOAc:hexane, 1:3) to give the title compound. After stirring for 18 h the mixture was filtered concentrated to a small volume partitioned between EtOAc and water The aqueous layer was extracted with EtOAc (2×50 mL) The combined organic phase was washed with aqueous saturated NaHCO3 solution, brine dried (Na2SO4) Filtration and concentration afforded a residue which was purified by flash chromatography (SiO2, EtOAc:hexane, 1:3)

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

Procedure: Glycine methyl ester hydrochloride (4.41 g, 0.035 mol) was dissolved in 1,2-dichloroethane (50 mL) and DMF (5 mL) and treated with 3A molecular sieves (10 g) and N-t-butoxycarbonyl-isoleucinal (6.3 g, 0.029 mol) with stirring at 0° C. Sodium triacetoxyborohydride (9.27 g, 0.044 mol) was added, and the pH of the mixture was adjusted to 6 with triethylamine (3 mL, 0.022 mol). After stirring for 18 h the mixture was filtered, concentrated to a small volume and partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic phase was washed with aqueous saturated NaHCO3 solution, brine, and dried (Na2SO4). Filtration and concentration afforded a residue which was purified by flash chromatography (SiO2, EtOAc:hexane, 1:3) to give the title compound. After stirring for 18 h the mixture was filtered concentrated to a small volume partitioned between EtOAc and water The aqueous layer was extracted with EtOAc (2×50 mL) The combined organic phase was washed with aqueous saturated NaHCO3 solution, brine dried (Na2SO4) Filtration and concentration afforded a residue which was purified by flash chromatography (SiO2, EtOAc:hexane, 1:3)

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:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of L-isoleucine methyl ester (24.3 g., 0.134 mmoles) and triethylamine (13.5 g., 0.134 mmoles) in methylene chloride (210 ml.) was prepared and a solution of ditertbutyldicarbonate (Aldrich, 29.1 g., 0.134 mmoles) in methylene chloride (25 ml.) was added dropwise to this mixture at 0° C. After completion of this addition, the mixture was allowed to warm to room temperature overnight and was then filtered. The filtrate was washed successively with water (1×100 ml.) and a saturated sodium bicarbonate solution (1×75 ml.), dried over magnesium sulfate and evaporated to yield N-(t-butoxycarbonyl)-L-isoleucine methyl ester as an oil [30.7 g.; 93% yield; 1H-NMR (CDCl3): delta 0.92 (d, J=7,6H), 1.43 (s, 9H), 3.70 (s, 3H), 4.17 (dd, J=5, 9, 1H), 5.03 (d, J=9, 1H)]. A solution of the N-(t-butoxycarbonyl)-L-isoleucine methyl ester oil (15.0 g., 61.1 mmoles) in dry toluene (260 ml.) was cooled to -78° C., and a 1M solution of diisobutyl aluminum hydride in hexane (153 ml.) was added dropwise thereto at such a rate that the temperature of the exothermic reaction did not exceed -65° C. Following 15 minutes of addition stirring at -78° C. after completion of this addition, the mixture was carefully quenched with 15 ml. of methanol (the mixture temperature was not allowed to exceed -65° C.) followed by 200 ml. of Rochelle salt solution. After warming to room temperature, the organic layer was separated and extracted with ether (3×200 ml.); additional Rochelle salt solution was added when necessary to dissolve the aluminum salts. The combined organic extract was dried over sodium sulfate and evaporated to afford a crude product as an oil. The oil was stored at -78° C. to avoid possible racemization and was used without purification in the next step [132 g., 98% yield, Rf=0.32 in 35% ether in hexane; 1H-NMR (CDCl3): delta 1.00 (d, J=7,6H), 1.46 (s, 9H), 9.65 (s, 1H)]. at such a rate that the temperature of the exothermic reaction did not exceed -65° C Following 15 minutes of addition after completion of this addition the mixture was carefully quenched with 15 ml to exceed -65° C. After warming to room temperature the organic layer was separated extracted with ether (3×200 ml.) additional Rochelle salt solution was added when necessary to dissolve the aluminum salts The combined organic extract was dried over sodium sulfate evaporated

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

Procedure: Isoleucine (1.31 g, 9.95 mmol) was suspended in anhydrous methanol (10 ml) and trifluoroacetic acid (1.133 g, 0.77 ml, 9.95 mmol) was added. The mixture was stirred until all the isoleucine had dissolved and the solvent was then removed under reduced pressure. Anhydrous DMF (10 ml) was added to the resulting isoleucine trifluoroacetate salt followed by 3 Å molecular sieves and a solution of 2 (1.47 g, 4.9 mmol) in anhydrous DMF (5 ml). After 15 minutes the solution was treated with sodium triacetoxy borohydride (1.58 g, 7.45 mmol) and stirred overnight. The resulting suspension was filtered through celite, diluted with ethyl acetate (50 ml) and washed with saturated sodium chloride solution (2×35 ml). The organic extracts were dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure to yield the acid (1.36 g, 84%) as a yellow oil. had dissolved the solvent was then removed under reduced pressure Anhydrous DMF (10 ml) was added to the resulting isoleucine trifluoroacetate salt The resulting suspension was filtered through celite diluted with ethyl acetate (50 ml) washed with saturated sodium chloride solution (2×35 ml) The organic extracts were dried over magnesium sulfate filtered the solvent removed under reduced pressure

Conditions: temp:-45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The Weinreb amide of N-t-butoxycarbonylisoleucine, prepared above, (1.98 g, 7.2 mmol) was dissolved in anhydrous ether (10 ml) and cooled to -45° C. Lithium aluminium hydride (10 ml of a 1N solution in ether, 10 mmol) was then added keeping the temperature below -35° C., after addition the solution was then allowed to warm to 5° C. The solution was then cooled to -45° C. and sodium sulfate decahydrate (5.00 g) added and the cooling bath removed. After 1 hour the solution was filtered through celite and the solvent removed under reduced pressure to yield the aldehyde (1.47 g, 95%) as a colourless oil, which was immediately used in the next reaction as it racemises at room temperature. the temperature below -35° C. after addition the solution to warm to 5° C The solution was then cooled to -45° C. the cooling bath removed After 1 hour the solution was filtered through celite the solvent removed under reduced pressure

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of L-isoleucine methyl ester (24.3 g., 0.134 mmoles) and triethylamine (13.5 g., 0.134 mmoles) in methylene chloride (210 ml.) was prepared and a solution of ditertbutyldicarbonate (Aldrich, 29.1 g., 0.134 mmoles) in methylene chloride (25 ml.) was added dropwise to this mixture at 0° C. After completion of this addition, the mixture was allowed to warm to room temperature overnight and was then filtered. The filtrate was washed successively with water (1×100 ml.) and a saturated sodium bicarbonate solution (1×75 ml.), dried over magnesium sulfate and evaporated to yield N-(t-butoxycarbonyl)-L-isoleucine methyl ester as an oil [30.7 g.; 93% yield; 1H-NMR (CDCl3): delta 0.92 (d, J=7,6H), 1.43 (s, 9H), 3.70 (s, 3H), 4.17 (dd, J=5, 9, 1H), 5.03 (d, J=9, 1H)]. A solution of the N-(t-butoxycarbonyl)-L-isoleucine methyl ester oil (15.0 g., 61.1 mmoles) in dry toluene (260 ml.) was cooled to -78° C., and a 1M solution of diisobutyl aluminum hydride in hexane (153 ml.) was added dropwise thereto at such a rate that the temperature of the exothermic reaction did not exceed -65° C. Following 15 minutes of addition stirring at -78° C. after completion of this addition, the mixture was carefully quenched with 15 ml. of methanol (the mixture temperature was not allowed to exceed -65° C.) followed by 200 ml. of Rochelle salt solution. After warming to room temperature, the organic layer was separated and extracted with ether (3×200 ml.); additional Rochelle salt solution was added when necessary to dissolve the aluminum salts. The combined organic extract was dried over sodium sulfate and evaporated to afford a crude product as an oil. The oil was stored at -78° C. to avoid possible racemization and was used without purification in the next step [132 g., 98% yield, Rf=0.32 in 35% ether in hexane; 1H-NMR (CDCl3): delta 1.00 (d, J=7,6H), 1.46 (s, 9H), 9.65 (s, 1H)]. at such a rate that the temperature of the exothermic reaction did not exceed -65° C Following 15 minutes of addition after completion of this addition the mixture was carefully quenched with 15 ml to exceed -65° C. After warming to room temperature the organic layer was separated extracted with ether (3×200 ml.) additional Rochelle salt solution was added when necessary to dissolve the aluminum salts The combined organic extract was dried over sodium sulfate evaporated

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of L-isoleucine methyl ester (24.3 g., 0.134 mmoles) and triethylamine (13.5 g., 0.134 mmoles) in methylene chloride (210 ml.) was prepared and a solution of ditertbutyldicarbonate (Aldrich, 29.1 g., 0.134 mmoles) in methylene chloride (25 ml.) was added dropwise to this mixture at 0° C. After completion of this addition, the mixture was allowed to warm to room temperature overnight and was then filtered. The filtrate was washed successively with H2O (3×75 ml.), aqueous 0.1N HCl solution, H2O (1×100 ml.) and saturated aqueous NaHCO3 solution (1×75 ml.), dried (MgSO4) and evaporated to yield N-(t-butyloxycarbonyl)-L -isoleucine methyl ester as an oil [30.7 g; 93% yield; lH-NMR (CDCl3): delta 0.92 (d, J=7, 6H), 1.43 (s, 9H), 3.70 (s, 3H), 4.17 (dd, J=5, 9, 1H), 5.03 (d, J=9, 1H)]. A solution of the N-(t-butyloxycarbonyl)-L-isoleucine methyl ester oil (15.0 g., 61.1 mmoles) in dry toluene (260 ml.) was cooled to -78° C., and a 1M solution of diisobutyl aluminum hydride in hexane (153 ml.) was added dropwise thereto at such a rate that the temperature of the exothermic reaction did not exceed -65° C. Followed by 15 minutes of additional stirring at -78° C. After completion of this addition, the mixture was carefully quenched with 15 ml. of methanol (the mixture temperature was not allowed to exceed -65° C.) followed by 200 ml. of Rochelle salt solution. After warming to room temperature, the organic layer was separated and extracted with ether (3×200 ml.); additional Rochelle salt solution was added when necessary to dissolve the aluminum salts. The combined organic extract was dried (Na2SO4 ) and evaporated to afford a crude product as an oil. The oil was stored at -78° C. to avoid possible racemization and was used without purification in the next step [132 g.; 98% yield; Rf =0.32 in 35% ether in hexane; 1H-NMR (CDCl3) delta 1.00 (d, J=7, 6 H), 1.46 (s, 9H), 9.65 (s, 1H)]. at such a rate that the temperature of the exothermic reaction did not exceed -65° C After completion of this addition the mixture was carefully quenched with 15 ml to exceed -65° C. After warming to room temperature the organic layer was separated extracted with ether (3×200 ml.) additional Rochelle salt solution was added when necessary to dissolve the aluminum salts The combined organic extract was dried (Na2SO4 ) evaporated

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of L-isoleucine methyl ester (24.3 g., 0.134 mmoles) and triethylamine (13.5 g., 0.134 mmoles) in methylene chloride (210 ml.) was prepared and a solution of ditertbutyldicarbonate (Aldrich, 29.1 g., 0.134 mmoles) in methylene chloride (25 ml.) was added dropwise to this mixture at 0° C. After completion of this addition, the mixture was allowed to warm to room temperature overnight and was then filtered. The filtrate was washed successively with H2O (3×75 ml.), aqueous 0.1N HCl solution, H2O (1×100 ml.) and saturated aqueous NaHCO3 solution (1×75 ml.), dried (MgSO4) and evaporated to yield N-(t-butyloxycarbonyl)-L -isoleucine methyl ester as an oil [30.7 g; 93% yield; lH-NMR (CDCl3): delta 0.92 (d, J=7, 6H), 1.43 (s, 9H), 3.70 (s, 3H), 4.17 (dd, J=5, 9, 1H), 5.03 (d, J=9, 1H)]. A solution of the N-(t-butyloxycarbonyl)-L-isoleucine methyl ester oil (15.0 g., 61.1 mmoles) in dry toluene (260 ml.) was cooled to -78° C., and a 1M solution of diisobutyl aluminum hydride in hexane (153 ml.) was added dropwise thereto at such a rate that the temperature of the exothermic reaction did not exceed -65° C. Followed by 15 minutes of additional stirring at -78° C. After completion of this addition, the mixture was carefully quenched with 15 ml. of methanol (the mixture temperature was not allowed to exceed -65° C.) followed by 200 ml. of Rochelle salt solution. After warming to room temperature, the organic layer was separated and extracted with ether (3×200 ml.); additional Rochelle salt solution was added when necessary to dissolve the aluminum salts. The combined organic extract was dried (Na2SO4 ) and evaporated to afford a crude product as an oil. The oil was stored at -78° C. to avoid possible racemization and was used without purification in the next step [132 g.; 98% yield; Rf =0.32 in 35% ether in hexane; 1H-NMR (CDCl3) delta 1.00 (d, J=7, 6 H), 1.46 (s, 9H), 9.65 (s, 1H)]. at such a rate that the temperature of the exothermic reaction did not exceed -65° C After completion of this addition the mixture was carefully quenched with 15 ml to exceed -65° C. After warming to room temperature the organic layer was separated extracted with ether (3×200 ml.) additional Rochelle salt solution was added when necessary to dissolve the aluminum salts The combined organic extract was dried (Na2SO4 ) evaporated

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

Procedure: Glycine methyl ester hydrochloride (4.41 g, 0.035 mol) was dissolved in 1,2-dichloroethane (50 mL) and DMF (5 mL) and treated with 3A molecular sieves (10 g) and N-t-butoxycarbonyl-isoleucinal (6.3 g, 0.029 mol) with stirring at 0° C. Sodium triacetoxyborohydride (9.27 g, 0.044 mol) was added, and the pH of the mixture was adjusted to 6 with triethylamine (3 mL, 0.022 mol). After stirring for 18 h the mixture was filtered, concentrated to a small volume and partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic phase was washed with aqueous saturated NaHCO3 solution, brine, and dried (Na2SO4). Filtration and concentration afforded a residue which was purified by flash chromatography (SiO2, EtOAc:hexane, 1:3) to give (6). After stirring for 18 h the mixture was filtered concentrated to a small volume partitioned between EtOAc and water The aqueous layer was extracted with EtOAc (2×50 mL) The combined organic phase was washed with aqueous saturated NaHCO3 solution, brine dried (Na2SO4) Filtration and concentration afforded a residue which was purified by flash chromatography (SiO2, EtOAc:hexane, 1:3)