hept-6-enal

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: 1.2 g of ethyl 2-[4-(2-aminoethyl)phenoxy]-2-methylpropionate [WO 92/10468, example 2, intermediate (c)] was dissolved in THF (20 mL). Hept6-enal (0.43 g) and 4A sieves (0.6 g ) were added. After 10 minutes, 0.25 g of sodium cyanoborohydride was added and the mixture stirred at room temperature for 50 minutes. The reaction mixture was poured into 5% aq. sodium carbonate and extracted with ethyl acetate. The organic extract was washed with brine, dried over MgSO4 and concentrated. Purification by flash chromatography (5-10% MeOH/CH2Cl2) gave 0.15 g of ethyl 2-[4-(2-amino-[6-heptenyl]ethyl) phenoxy]-2-methylpropionate as a light brown viscous oil. This material was dissolved in CH2Cl2 (5 mL) and 4-fluorophenylisocyanate (0.05 mL) was added. The solution was stirred at rt for 3 hours and then concentrated. Purification by flash chromatography gave 0.08 g of ethyl 2-(4-[2-(3-[4-fluorophenyl]-1-[6-heptenyl]ureido) ethyl]phenoxy)-2-methylpropionate as a yellow solid. This material was dissolved in EtOH (3 mL) and 1M aq. NaOH (1.5 mL), and the solution was heated at reflux for 30 min. The solution was concentrated, poured into 1N HCl and extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated to a yellow solid. Recrystallization fron ether/hexane gave 0.05 g of 2-(4-[2-(3-[4-fluorophenyl]-1-[6-heptenyl]ureido)ethyl]phenoxy)-2- methylpropionic acid as a white powder; m.p. 143-5 degC. extracted with ethyl acetate The organic extract was washed with brine dried over MgSO4 concentrated Purification by flash chromatography (5-10% MeOH/CH2Cl2)

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: To a solution of compound 2 (68 mg, 0.610 mmol) and tert-butyl carbazate (81 mg, 0.613 mmol) in MeOH (5 mL) was added ground molecular sieves (115 mg, 3 Å). The mixture was stirred for 3 h after which it was filtered through celite and evaporated. The residue was dissolved in dry THF (3 mL) and AcOH (3 mL). NaBH3CN (95 mg, 1.51 mmol) was added and the solution was stirred over night. The reaction mixture was diluted with saturated NaHCO3 solution (6 mL) and EtOAc (6 mL). The organic phase was washed with brine, saturated NaHCO3, brine, dried over MgSO4 and evaporated. The cyanoborane adduct was hydrolyzed by treatment with MeOH (3 mL) and 2 M NaOH (1.9 mL). The mixture was stirred for 2 h and the MeOH was evaporated. H2O (5 mL) and DCM (5 mL) were added and the water phase was extracted three times with DCM. The combined organic phases were dried and evaporated. Purification by flash column chromatography (toluene/ethyl acetate 9:1 with 1% triethylamine and toluene/ethyl acetate 6:1 with 1% triethylamine) provided the title compound (85 mg, 61%) as an oil. was filtered through celite evaporated The residue was dissolved in dry THF (3 mL) the solution was stirred over night The organic phase was washed with brine, saturated NaHCO3, brine dried over MgSO4 evaporated The mixture was stirred for 2 h the MeOH was evaporated H2O (5 mL) and DCM (5 mL) were added the water phase was extracted three times with DCM The combined organic phases were dried evaporated Purification by flash column chromatography (toluene/ethyl acetate 9:1 with 1% triethylamine and toluene/ethyl acetate 6:1 with 1% triethylamine)

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

Procedure: Pyridinium chlorochromate (19.26 g, 0.088 mol) was added to a solution of hept-6-en-1-ol (5.0 g, 0.044 mol) and dichloromethane (600 mL). The resulting mixture was stirred at room temperature for 2 h, then diluted with diethyl ether, filtered through silica gel and concentrated in vacuo below room temperature to yield hept-6-enal as an oil, which was used in the next step without further purification. To a solution of hept-6-enal (4.9 g, 0.044 mol) in ethyl acetate (36 mL) was added a solution of sodium cyanide (6.4 g, 0.13 mol) in water (36 mL) and the resulting mixture was stirred at room temperature for 24 h. The layers were separated and the aqueous layer was extracted 2 times with ethyl acetate. The combined organic layers were dried (MgSO4) filtered and concentrated in vacuo to yield 2-hydroxyoct-7-enenitrile as a tan oil, which was used in the next step without further purification. A stream of HCl(g) was introduced into a solution of 2-hydroxyoct-7-enenitrile (6.0 g, 0.043 mmol) and methanol (130 mL) at −78° C. for 5 min. The resulting mixture was stored at −10° C. for 18 h, then concentrated in vacuo. The residue was diluted with ethyl acetate (106 mL) and water (106 mL) and the solution was stirred at room temperature overnight. The layers were separated, and the organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield methyl 2-hydroxyoct-7-enoate. 1H NMR (400 MHz, CDCl3) δ 5.48-5.82 (m, 1H), 4.89-5.08 (m, 2H), 4.31-4.52 (m, 1H), 3.79 (s, 3H), 2.78-3.12 (bs, 1H), 2.02-2.28 (m, 2H), 1.75-1.89 (m, 1H), 1.68-1.70 (m, 1H), and 1.38-1.52 (m, 4H). was used in the next step without further purification The layers were separated the aqueous layer was extracted 2 times with ethyl acetate The combined organic layers were dried (MgSO4) filtered concentrated in vacuo

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

Procedure: Pyridinium chlorochromate (19.26 g, 0.088 mol) was added to a solution of hept-6-en-1-ol (5.0 g, 0.044 mol) and dichloromethane (600 mL). The resulting mixture was stirred at room temperature for 2 h, then diluted with diethyl ether, filtered through silica gel and concentrated in vacuo below room temperature to yield hept-6-enal as an oil, which was used in the next step without further purification. To a solution of hept-6-enal (4.9 g, 0.044 mol) in ethyl acetate (36 mL) was added a solution of sodium cyanide (6.4 g, 0.13 mol) in water (36 mL) and the resulting mixture was stirred at room temperature for 24 h. The layers were separated and the aqueous layer was extracted 2 times with ethyl acetate. The combined organic layers were dried (MgSO4) filtered and concentrated in vacuo to yield 2-hydroxyoct-7-enenitrile as a tan oil, which was used in the next step without further purification. A stream of HCl(g) was introduced into a solution of 2-hydroxyoct-7-enenitrile (6.0 g, 0.043 mmol) and methanol (130 mL) at −78° C. for 5 min. The resulting mixture was stored at −10° C. for 18 h, then concentrated in vacuo. The residue was diluted with ethyl acetate (106 mL) and water (106 mL) and the solution was stirred at room temperature overnight. The layers were separated, and the organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield methyl 2-hydroxyoct-7-enoate. 1H NMR (400 MHz, CDCl3) δ 5.48-5.82 (m, 1H), 4.89-5.08 (m, 2H), 4.31-4.52 (m, 1H), 3.79 (s, 3H), 2.78-3.12 (bs, 1H), 2.02-2.28 (m, 2H), 1.75-1.89 (m, 1H), 1.68-1.70 (m, 1H), and 1.38-1.52 (m, 4H). was used in the next step without further purification The layers were separated the aqueous layer was extracted 2 times with ethyl acetate The combined organic layers were dried (MgSO4) filtered concentrated in vacuo

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

Procedure: 1.2 g of ethyl 2-[4-(2-aminoethyl)phenoxy]-2-methylpropionate [WO 92/10468, example 2, intermediate (c)] was dissolved in THF (20 mL). Hept6-enal (0.43 g) and 4A sieves (0.6 g ) were added. After 10 minutes, 0.25 g of sodium cyanoborohydride was added and the mixture stirred at room temperature for 50 minutes. The reaction mixture was poured into 5% aq. sodium carbonate and extracted with ethyl acetate. The organic extract was washed with brine, dried over MgSO4 and concentrated. Purification by flash chromatography (5-10% MeOH/CH2Cl2) gave 0.15 g of ethyl 2-[4-(2-amino-[6-heptenyl]ethyl) phenoxy]-2-methylpropionate as a light brown viscous oil. This material was dissolved in CH2Cl2 (5 mL) and 4-fluorophenylisocyanate (0.05 mL) was added. The solution was stirred at rt for 3 hours and then concentrated. Purification by flash chromatography gave 0.08 g of ethyl 2-(4-[2-(3-[4-fluorophenyl]-1-[6-heptenyl]ureido) ethyl]phenoxy)-2-methylpropionate as a yellow solid. This material was dissolved in EtOH (3 mL) and 1M aq. NaOH (1.5 mL), and the solution was heated at reflux for 30 min. The solution was concentrated, poured into 1N HCl and extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated to a yellow solid. Recrystallization fron ether/hexane gave 0.05 g of 2-(4-[2-(3-[4-fluorophenyl]-1-[6-heptenyl]ureido)ethyl]phenoxy)-2- methylpropionic acid as a white powder; m.p. 143-5 degC. extracted with ethyl acetate The organic extract was washed with brine dried over MgSO4 concentrated Purification by flash chromatography (5-10% MeOH/CH2Cl2)

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

Procedure: To a solution of 46 (68 mg, 0.610 mmol) and tert-butyl carbazate (81 mg, 0.613 mmol) in MeOH (5 mL) was added ground molecular sieves (115 mg, 3A). The mixture was stirred for 3 h after which it was filtered through celite and evaporated. The residue was dissolved in dry THF (3 mL) and AcOH (3 mL). NaBH3CN (95 mg, 1.51 mmol) was added and the solution was stirred over night. The reaction mixture was diluted with saturated NaHCO3 solution (6 mL) and EtOAc (6 mL). The organic phase washed with brine, saturated NaHCO3, brine, dried over MgSO4 and evaporated. The cyanoborane adduct was hydrolyzed by treatment with MeOH (3 mL) and 2 M NaOH (1.9 mL). The mixture was stirred for 2 h and the MeOH was evaporated. H2O (5 mL) and DCM (5 mL) were added and the water phase was extracted three times with DCM. The combined organic phases were dried and evaporated. Purification by flash column chromatography (toluene/ethyl acetate 9:1 with 1% triethylamine and toluene/ethyl acetate 6:1 with 1% triethylamine) provided 47 (85 mg, 61%) as an oil. was filtered through celite evaporated The residue was dissolved in dry THF (3 mL) the solution was stirred over night The organic phase washed with brine, saturated NaHCO3, brine dried over MgSO4 evaporated The mixture was stirred for 2 h the MeOH was evaporated H2O (5 mL) and DCM (5 mL) were added the water phase was extracted three times with DCM The combined organic phases were dried evaporated Purification by flash column chromatography (toluene/ethyl acetate 9:1 with 1% triethylamine and toluene/ethyl acetate 6:1 with 1% triethylamine)

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

Procedure: To a solution of 46 (68 mg, 0.610 mmol) and tert-butyl carbazate (81 mg, 0.613 mmol) in MeOH (5 mL) was added ground molecular sieves (115 mg, 3A). The mixture was stirred for 3 h after which it was filtered through celite and evaporated. The residue was dissolved in dry THF (3 mL) and AcOH (3 mL). NaBH3CN (95 mg, 1.51 mmol) was added and the solution was stirred over night. The reaction mixture was diluted with saturated NaHCO3 solution (6 mL) and EtOAc (6 mL). The organic phase washed with brine, saturated NaHCO3, brine, dried over MgSO4 and evaporated. The cyanoborane adduct was hydrolyzed by treatment with MeOH (3 mL) and 2 M NaOH (1.9 mL). The mixture was stirred for 2 h and the MeOH was evaporated. H2O (5 mL) and DCM (5 mL) were added and the water phase was extracted three times with DCM. The combined organic phases were dried and evaporated. Purification by flash column chromatography (toluene/ethyl acetate 9:1 with 1% triethylamine and toluene/ethyl acetate 6:1 with 1% triethylamine) provided 47 (85 mg, 61%) as an oil. was filtered through celite evaporated The residue was dissolved in dry THF (3 mL) the solution was stirred over night The organic phase washed with brine, saturated NaHCO3, brine dried over MgSO4 evaporated The mixture was stirred for 2 h the MeOH was evaporated H2O (5 mL) and DCM (5 mL) were added the water phase was extracted three times with DCM The combined organic phases were dried evaporated Purification by flash column chromatography (toluene/ethyl acetate 9:1 with 1% triethylamine and toluene/ethyl acetate 6:1 with 1% triethylamine)

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

Procedure: Following the procedure described above for Compound 19 Steps 1-2, treatment of methyl (3S)-3-methyl-L-prolinate with hept-6-enal afforded the title compound 125 (80%) as an oil. 1H NMR (400 MHz, DMSO-d6, 300 K) δ 5.78 (m, 1H), 5.03-4.92 (m, 2H), 3.58-3.48 (m, 2H), 3.19-3.01 (m, 2H), 3.07-2.95 (m, 1H), 2.34-2.22 (m, 1H), 2.12-2.00 (m, 3H), 1.69-1.55 (m, 3H), 1.41-1.22 (m, 4H), 1.18 (d, J 8.8, 3H).

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

Procedure: To a solution (0.3M) of L-valine, methyl ester, hydrochloride in dry MeOH was added ZnCl2 (1.0 eq.), NaCNBH3 (1.2 eq.), hept-6-enal 66 (1.2 eq.), and the reaction mixture was stirred at RT overnight. Then the volatiles were evaporated at reduced pressure and the residue taken-up in CH2Cl2 and washed with a saturated aq. solution of NaHCO3. The organic layer was dried over Na2SO4 and evaporated at reduced pressure affording the title compound (98%) as yellow pale oil. Then the volatiles were evaporated at reduced pressure the residue taken-up in CH2Cl2 and washed with a saturated aq. solution of NaHCO3 The organic layer was dried over Na2SO4 evaporated at reduced pressure