(Z)-4-methylpent-2-enal

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

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

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 a mixture of 4-methyl-2-(5-piperidin-4-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester and methyl ester (68b) (60 mg, 0.13 mmol) in 1,2-dichloroethane (2.0 mL) was added 4-methyl-pent-2-enal (15 mg, 0.15 mmol) and sodiumtriacetoxyborohydride (37 mg, 0.17 mmol). The mixture was stirred for 2 h at room temperature. The reaction was quenched with water and extracted with dichloromethane. The organic was washed with saturated aqueous NaHCO3 solution and brine. The organic fraction was dried (MgSO4) and concentrated in vacuo. The crude mixture contained 4-methyl-2-{5-[1-(4-methyl-pent-2-enyl)-piperidin-4-yl]-4′-trifluoromethyl-biphenyl-3-yl}-pentanoic acid ethyl and methyl ester. Calcd for C31H40F3NO2 (M+H) 516.65, Found 516.30 (methyl ester) and Calcd for C32H42F3NO2 (M+H) 530.68, Found 531.24 (ethyl ester). The reaction was quenched with water extracted with dichloromethane The organic was washed with saturated aqueous NaHCO3 solution and brine The organic fraction was dried (MgSO4) concentrated in vacuo

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

Procedure: To a solution of a mixture of 4-methyl-2-(5-piperidin-4-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester and methyl ester (68b) (60 mg, 0.13 mmol) in 1,2-dichloroethane (2.0 mL) was added 4-methyl-pent-2-enal (15 mg, 0.15 mmol) and sodiumtriacetoxyborohydride (37 mg, 0.17 mmol). The mixture was stirred for 2 h at room temperature. The reaction was quenched with water and extracted with dichloromethane. The organic was washed with saturated aqueous NaHCO3 solution and brine. The organic fraction was dried (MgSO4) and concentrated in vacuo. The crude mixture contained 4-methyl-2-{5-[1-(4-methyl-pent-2-enyl)-piperidin-4-yl]-4′-trifluoromethyl-biphenyl-3-yl}-pentanoic acid ethyl and methyl ester. Calcd for C31H40F3NO2 (M+H) 516.65, Found 516.30 (methyl ester) and Calcd for C32H42F3NO2 (M+H) 530.68, Found 531.24 (ethyl ester). The reaction was quenched with water extracted with dichloromethane The organic was washed with saturated aqueous NaHCO3 solution and brine The organic fraction was dried (MgSO4) concentrated in vacuo

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

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

Procedure: The compounds were prepared according to the procedure described in Example 84 except that the reaction was worked up after 3 days. The following reagents were used: 1-(4-methoxyphenyl)-2-methylpropanone (17.8 g), diisopropylamine (32.2 mL), 1.6M 1-butyl lithium in hexane (143 mL), acetaldehyde N-tert-butylimine (14.75 mL), diethyl chlorophosphonate (16.6 mL) and tetrahydrofuran (200 mL). The work up, varied only in that the oxalic acid hydrolysis was run overnight at room temperature, furnished 21.3 g of crude product containing (E)- and (Z)-3-4-methoxyphenyl)-4-methyl-2-pentenal in the ratio of 2:3. An attempt to separate the crude by HPLC (ether-hexane; 3:17; multiple recycles) only resulted in mixtures of (E)-3-(4-methoxphenyl)-4-methyl-2-pentenal and (Z)-3-(4-methoxyphenyl)-4-methyl-2-pentenal with E/Z ratios that varied between 1:and 1:1. The compounds were prepared was run overnight at room temperature furnished 21.3 g of crude product An attempt to separate the crude by HPLC (ether-hexane; 3:17; multiple recycles)

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

Procedure: The compounds were prepared according to the procedure described in Example 84 except that the reaction was worked up after 3 days. The following reagents were used: 1-(4-methoxyphenyl)-2-methylpropanone (17.8 g), diisopropylamine (32.2 mL), 1.6M 1-butyl lithium in hexane (143 mL), acetaldehyde N-tert-butylimine (14.75 mL), diethyl chlorophosphonate (16.6 mL) and tetrahydrofuran (200 mL). The work up, varied only in that the oxalic acid hydrolysis was run overnight at room temperature, furnished 21.3 g of crude product containing (E)- and (Z)-3-4-methoxyphenyl)-4-methyl-2-pentenal in the ratio of 2:3. An attempt to separate the crude by HPLC (ether-hexane; 3:17; multiple recycles) only resulted in mixtures of (E)-3-(4-methoxphenyl)-4-methyl-2-pentenal and (Z)-3-(4-methoxyphenyl)-4-methyl-2-pentenal with E/Z ratios that varied between 1:and 1:1. The compounds were prepared was run overnight at room temperature furnished 21.3 g of crude product An attempt to separate the crude by HPLC (ether-hexane; 3:17; multiple recycles)

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

Procedure: Prepared according to the general procedure from 4-methyl-2-pentenal (175 μL, 1.50 mmol), 1-methyl-1H-indole (64 μL, 0.50 mmol), TFA (7.7 μL, 0.10 mmol) and (2S,5S)-5-benzyl-2-tert-butyl-3-methyl-imidazolidin-4-one (24.6 mg, 0.100 mmol) in CH2Cl2 (0.90 mL) and isopropanol (0.10 mL) at −50° C. for 32 h to provide, after silica gel chromatography (10:90 EtOAc/hexanes), the title compound as a colorless oil (85 mg, 74% yield, 93% ee). IR (film) 3052, 2958, 2870, 2834, 2716, 1723, 1609, 1546, 1482, 1469, 1423, 1373, 1328, 1246, 1160, 1138, 1015, 743 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.61 (dd, J=2.4, 2.4 Hz, 1H, CHO), 7.63 (dt, J=0.9, 8.1 Hz, 1H, ArH), 7.33-7.22 (m, 2H, ArH), 7.13 (ddd, J=1.5, 6.9, 8.1 Hz, 1H, ArH), 6.82 (s, 1H, NCH), 3.75 (s, 3H, NCH3), 3.40 (dt, J=6.6, 7.8 Hz, 1H, ArCH), 2.81 (d, J=2.4 Hz, 1H, CH2CO); 2.79 (d, J=2.4 Hz, 1H, CH2CO); 2.10 (ddd, J=6.6, 13.2, 19.8 Hz, 1H, CH(CH3)2, 0.96 (d, J=2.1, 3H, CH(CH3)2, 0.94 (d, J=2.1 Hz, 3H, CH(CH3)2; 13C NMR (75 MHz, CDCl3) δ 203.4, 137.0, 127.6, 126.7, 121.6, 119.4, 118.8, 115.6, 109.3, 46.1, 38.0, 32.9, 32.9, 20.6, 20.4; HRMS (CI) exact mass calcd for (C15H19NO) requires m/z 229.1467, found m/z 229.1465. [α]D=+15.8 (c=1.0, CHCl3). The enantiomeric ratio was determined by HPLC analysis of the alcohol, obtained by NaBH4 reduction of the aldehyde, using a Chiracel AS and AS guard column (4% ethanol/hexanes, 1 mL/min); R isomer tr=13.4 min and S isomer tr=16.7 min. Prepared to provide

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

Procedure: To a solution of a mixture of 4-methyl-2-(5-piperidin-4-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester and methyl ester (68b) (60 mg, 0.13 mmol) in 1,2-dichloroethane (2.0 mL) was added 4-methyl-pent-2-enal (15 mg, 0.15 mmol) and sodiumtriacetoxyborohydride (37 mg, 0.17 mmol). The mixture was stirred for 2 h at room temperature. The reaction was quenched with water and extracted with dichloromethane. The organic was washed with saturated aqueous NaHCO3 solution and brine. The organic fraction was dried (MgSO4) and concentrated in vacuo. The crude mixture contained 4-methyl-2-{5-[1-(4-methyl-pent-2-enyl)-piperidin-4-yl]-4′-trifluoromethyl-biphenyl-3-yl}-pentanoic acid ethyl and methyl ester. Calcd for C31H40F3NO2 (M+H) 516.65, Found 516.30 (methyl ester) and Calcd for C32H42F3NO2 (M+H) 530.68, Found 531.24 (ethyl ester). The reaction was quenched with water extracted with dichloromethane The organic was washed with saturated aqueous NaHCO3 solution and brine The organic fraction was dried (MgSO4) concentrated in vacuo