tert-butyl (2S)-2-(2-hydroxyethyl)piperidine-1-carboxylate

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

Procedure: To a solution of (S)—N-Boc-piperidine-2-ethanol (1.00 g, 4.36 mmol), 4-hydroxydiphenylmethane (0.884 g, 4.79 mmol), and triphenylphosphine (1.26 g, 4.80 mmol) in anhydrous tetrahydrofuran (40 mL) at 0° C. under an atmosphere of nitrogen was added diisopropyl azodicarboxylate (0.92 ml, 4.80 mmol), and the resulting mixture was stirred at ambient temperature for about 20 h. The clear, yellow solution was concentrated in vacuo. The crude liquid was purified by silica gel flash chromatography to obtain the title compound as a clear, yellow oil (1.20 g, 70%): 1H NMR (400 MHz; CDCl3) δ 7.35 (m, 2H), 7.17 (m, 3H), 7.07 (d, 2H, J=8.8 Hz), 6.79 (d, 2H, J=8.8 Hz), 4.46 (m, 1H), 3.97 (m, 5H), 2.80 (br t, 1H, J=13.2 Hz), 2.12 (m, 1H), 1.85 (m, 1H), 1.60 (m, 5H), 1.40 (m, 10H). MS, m/z 418 (M+Na)+. The clear, yellow solution was concentrated in vacuo The crude liquid was purified by silica gel flash chromatography

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

Procedure: To a solution of (S)—N-Boc-piperidine-2-ethanol (1.00 g, 4.36 mmol), 4-hydroxydiphenylmethane (0.884 g, 4.79 mmol), and triphenylphosphine (1.26 g, 4.80 mmol) in anhydrous tetrahydrofuran (40 mL) at 0° C. under an atmosphere of nitrogen was added diisopropyl azodicarboxylate (0.92 ml, 4.80 mmol), and the resulting mixture was stirred at ambient temperature for about 20 h. The clear, yellow solution was concentrated in vacuo. The crude liquid was purified by silica gel flash chromatography to obtain the title compound as a clear, yellow oil (1.20 g, 70%): 1H NMR (400 MHz; CDCl3) δ 7.35 (m, 2H), 7.17 (m, 3H), 7.07 (d, 2H, J=8.8 Hz), 6.79 (d, 2H, J=8.8 Hz), 4.46 (m, 1H), 3.97 (m, 5H), 2.80 (br t, 1H, J=13.2 Hz), 2.12 (m, 1H), 1.85 (m, 1H), 1.60 (m, 5H), 1.40 (m, 10H). MS, m/z 418 (M+Na)+. The clear, yellow solution was concentrated in vacuo The crude liquid was purified by silica gel flash chromatography

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

Procedure: This compound is prepared in a manner analogous to that described in Example 3, but 1-Boc-piperidine is used insead of 1-Boc-pyrrolidine, and (+)-sparteine surrogate is used instead of (−)-sparteine. This compound is prepared in a manner analogous to

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

Procedure: This compound is prepared in a manner analogous to that described in Example 3, but 1-Boc-piperidine is used insead of 1-Boc-pyrrolidine, and (+)-sparteine surrogate is used instead of (−)-sparteine. This compound is prepared in a manner analogous to

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

Procedure: To a solution of (S)-2-(2-hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (0.300 g, 1.30 mmol) in dichloromethane (5 mL) was added methane sulfonylchloride 0.304 mL, 3.9 mmol) and triethylamine (0.547 mL, 3.9 mmol) at rt for 1-16 h. The reaction mixture was diluted with dichloromethane and washed with NaHCO3 (10%, W/V), followed by water. The dichloromethane layer was dried (Na2SO4), filtered and the solvent was evaporated to dryness. The product was sufficiently pure for the next step and was used without any further purification. LC-MS [M+Na] 329.9 washed with NaHCO3 (10%, W/V) The dichloromethane layer was dried (Na2SO4) filtered the solvent was evaporated to dryness was used without any further purification

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

Procedure: To a solution of (S)-2-(2-hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (0.300 g, 1.30 mmol) in dichloromethane (5 mL) was added methane sulfonylchloride 0.304 mL, 3.9 mmol) and triethylamine (0.547 mL, 3.9 mmol) at rt for 1-16 h. The reaction mixture was diluted with dichloromethane and washed with NaHCO3 (10%, W/V), followed by water. The dichloromethane layer was dried (Na2SO4), filtered and the solvent was evaporated to dryness. The product was sufficiently pure for the next step and was used without any further purification. LC-MS [M+Na] 329.9. washed with NaHCO3 (10%, W/V) The dichloromethane layer was dried (Na2SO4) filtered the solvent was evaporated to dryness was used without any further purification

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

Procedure: To a solution of (S)—N-Boc-piperidine-2-ethanol (1.00 g, 4.36 mmol), 4-hydroxydiphenylmethane (0.884 g, 4.79 mmol), and triphenylphosphine (1.26 g, 4.80 mmol) in anhydrous tetrahydrofuran (40 mL) at 0° C. under an atmosphere of nitrogen was added diisopropyl azodicarboxylate (0.92 ml, 4.80 mmol), and the resulting mixture was stirred at ambient temperature for about 20 h. The clear, yellow solution was concentrated in vacuo. The crude liquid was purified by silica gel flash chromatography to obtain the title compound as a clear, yellow oil (1.20 g, 70%): 1H NMR (400 MHz; CDCl3): δ 7.35 (m, 2H), 7.17 (m, 3H), 7.07 (d, 2H, J=8.8 Hz), 6.79 (d, 2H, J=8.8 Hz), 4.46 (m, 1H), 3.97 (m, 5H), 2.80 (br t, 1H, J=13.2 Hz), 2.12 (m, 1H), 1.85 (m, 1H), 1.60 (m, 5H), 1.40 (m, 10H). MS; m/z 418 (M+Na)+. The clear, yellow solution was concentrated in vacuo The crude liquid was purified by silica gel flash chromatography

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

Procedure: To a slurry of lithium aluminum hydride (580 mg in 65 mL dry diethyl ether) at 0° C. was added dropwise a solution of (S)-2-(methoxycarbonylmethyl)piperidine-1-carboxylic acid tert-butyl ester (5.47 g in 40 mL dry diethyl ether) over a period of 30 minutes. The reaction was allowed to continue at 0° C. for an additional hour, at which time it was quenched by the careful addition of 0.58 mL water followed by 0.58 mL 2N sodium hydroxide and 1.8 mL water. The resulting suspension was stirred vigorously for 30 minutes then filtered through diatomaceous earth. The filtrate was concentrated in vacuo and the residue purified by flash chromatography on silica gel (hexane:ethyl acetate, 6:4) to give the title compound (4.61 g). to continue at 0° C. for an additional hour, at which time it was quenched by the careful addition of 0.58 mL water then filtered through diatomaceous earth The filtrate was concentrated in vacuo the residue purified by flash chromatography on silica gel (hexane:ethyl acetate, 6:4)

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

Procedure: To a solution of (S)-2-(2-hydroxyethyl)-piperidine-1-carboxylic acid tert-butyl ester (0.864 g in 38 mL dry tetrahydrofuran) was added 1.56 g of 7-chloro-3-(3,5-dimethylphenyl)-4-hydroxy-6-nitro-1H-quinolin-2-one [see Example 9] followed by 1.19 g of triphenylphosphine and the mixture stirred at room temperature. To this was added 0.72 mL of diethyl azodicarboxylate (DEAD) and stirring was continued for 64 hours. At this time the solvents were removed in vacuo and the residue purified by flash chromatography on silica gel (hexane:ethyl acetate, 6:4) to give the title compound, 1.56 g. stirring At this time the solvents were removed in vacuo the residue purified by flash chromatography on silica gel (hexane:ethyl acetate, 6:4)

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

Procedure: To a solution of (S)—N-Boc-piperidine-2-ethanol (1.00 g, 4.36 mmol), 4-hydroxydiphenylmethane (0.884 g, 4.79 mmol), and triphenylphosphine (1.26 g, 4.80 mmol) in anhydrous tetrahydrofuran (40 mL) at 0° C. under an atmosphere of nitrogen was added diisopropyl azodicarboxylate (0.92 ml, 4.80 mmol), and the resulting mixture was stirred at ambient temperature for about 20 h. The clear, yellow solution was concentrated in vacuo. The crude liquid was purified by silica gel flash chromatography to obtain the title compound as a clear, yellow oil (1.20 g, 70%): 1H NMR (400 MHz; CDCl3) δ 7.35 (m, 2H), 7.17 (m, 3H), 7.07 (d, 2H, J=8.8 Hz), 6.79 (d, 2H, J=8.8 Hz), 4.46 (m, 1H), 3.97 (m, 5H), 2.80 (br t, 1H, J=13.2 Hz), 2.12 (m, 1H), 1.85 (m, 1H), 1.60 (m, 5H), 1.40 (m, 10H). MS, m/z 418 (M+Na)+. The clear, yellow solution was concentrated in vacuo The crude liquid was purified by silica gel flash chromatography

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

Procedure: This compound is prepared in a manner analogous to that described in Example 3, but 1-Boc-piperidine is used insead of 1-Boc-pyrrolidine, and (+)-sparteine surrogate is used instead of (−)-sparteine. This compound is prepared in a manner analogous to

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

Procedure: To a solution of (S)-2-(2-hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (0.300 g, 1.30 mmol) in dichloromethane (5 mL) was added methane sulfonylchloride 0.304 mL, 3.9 mmol) and triethylamine (0.547 mL, 3.9 mmol) at rt for 1-16 h. The reaction mixture was diluted with dichloromethane and washed with NaHCO3 (10%, W/V), followed by water. The dichloromethane layer was dried (Na2SO4), filtered and the solvent was evaporated to dryness. The product was sufficiently pure for the next step and was used without any further purification. LC-MS [M+Na] 329.9 washed with NaHCO3 (10%, W/V) The dichloromethane layer was dried (Na2SO4) filtered the solvent was evaporated to dryness was used without any further purification