(2R)-1-phenylmethoxypent-4-en-2-ol

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

Procedure: This reaction was carried out in two identical experiments. To a 0° C. suspension of sodium hydride (60% in mineral oil, 125 g, 3.12 mol) in tetrahydrofuran (1 L) was added a solution of C1 (200 g, 1.04 mol) in tetrahydrofuran (500 mL). The reaction was stirred for 30 minutes at room temperature, whereupon 2-bromo-1,1-diethoxyethane (528 g, 2.68 mol) was added, and the reaction mixture was heated at reflux for 18 hours. The mixture was carefully quenched with water (2×300 mL) and the combined experiments were concentrated in vacuo. The aqueous residue was partitioned between ethyl acetate (5 L) and water (5 L). The organic layer was washed with saturated aqueous sodium chloride solution (5 L), dried, and concentrated. Purification via silica gel chromatography (Eluent: 20:1 petroleum ether/ethyl acetate) provided the product as a yellow oil. Yield: 300 g, 0.97 mol, 47%. 1H NMR (400 MHz, CDCl3) δ 7.26-7.37 (m, 5H), 5.78-5.90 (m, 1H), 5.01-5.13 (m, 2H), 4.61 (t, J=5.3 Hz, 1H), 4.55 (s, 2H), 3.48-3.74 (m, 9H), 2.30-2.36 (m, 2H), 1.22 (t, J=7.1 Hz, 3H), 1.21 (t, J=7.0 Hz, 3H). was added the reaction mixture was heated at reflux for 18 hours The mixture was carefully quenched with water (2×300 mL) the combined experiments were concentrated in vacuo The aqueous residue was partitioned between ethyl acetate (5 L) and water (5 L) The organic layer was washed with saturated aqueous sodium chloride solution (5 L) dried concentrated Purification via silica gel chromatography (Eluent: 20:1 petroleum ether/ethyl acetate)

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

Procedure: To a solution of (2R)-2-[(benzyloxy)methyl]oxirane (167 g, 1.02 mol) in tetrahydrofuran (2 L) was added copper(I) iodide (11.62 g, 61.02 mmol) at room temperature. The mixture was stirred for 5 minutes, then cooled to −78° C. A solution of vinylmagnesium bromide (1 M in tetrahydrofuran, 1.12 L, 1.12 mol) was added drop-wise over 1 hour while the reaction temperature was maintained below −70° C. Upon completion of the addition, the cooling bath was removed and the reaction mixture was left to stir at room temperature for 1 hour, then quenched by slow addition of aqueous ammonium chloride solution (200 mL). After dilution with aqueous ammonium chloride solution (1.5 L) and ethyl acetate (1.5 L), the aqueous layer was extracted with ethyl acetate (1 L) and the combined organic layers were washed with aqueous ammonium chloride solution (1.5 L), dried over magnesium sulfate, filtered, and concentrated in vacuo. Three batches of this reaction were carried out and combined to give the product as an orange oil. Yield: 600 g, 3.1 mol, quantitative. 1H NMR (400 MHz, CDCl3) δ 7.28-7.40 (m, 5H), 5.78-5.90 (m, 1H), 5.08-5.17 (m, 2H), 4.57 (s, 2H), 3.86-3.94 (m, 1H), 3.53 (dd, J=9.6, 3.3 Hz, 1H), 3.39 (dd, J=9.6, 7.4 Hz, 1H), 2.26-2.34 (m, 3H). was maintained below −70° C Upon completion of the addition the cooling bath was removed the reaction mixture was left to stir at room temperature for 1 hour quenched by slow addition of aqueous ammonium chloride solution (200 mL) After dilution with aqueous ammonium chloride solution (1.5 L) and ethyl acetate (1.5 L), the aqueous layer was extracted with ethyl acetate (1 L) the combined organic layers were washed with aqueous ammonium chloride solution (1.5 L) dried over magnesium sulfate filtered concentrated in vacuo

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

Procedure: To a solution of (2R)-2-[(benzyloxy)methyl]oxirane (167 g, 1.02 mol) in tetrahydrofuran (2 L) was added copper(I) iodide (11.62 g, 61.02 mmol) at room temperature. The mixture was stirred for 5 minutes, then cooled to −78° C. A solution of vinylmagnesium bromide (1 M in tetrahydrofuran, 1.12 L, 1.12 mol) was added drop-wise over 1 hour while the reaction temperature was maintained below −70° C. Upon completion of the addition, the cooling bath was removed and the reaction mixture was left to stir at room temperature for 1 hour, then quenched by slow addition of aqueous ammonium chloride solution (200 mL). After dilution with aqueous ammonium chloride solution (1.5 L) and ethyl acetate (1.5 L), the aqueous layer was extracted with ethyl acetate (1 L) and the combined organic layers were washed with aqueous ammonium chloride solution (1.5 L), dried over magnesium sulfate, filtered, and concentrated in vacuo. Three batches of this reaction were carried out and combined to give the product as an orange oil. Yield: 600 g, 3.1 mol, quantitative. 1H NMR (400 MHz, CDCl3) δ 7.28-7.40 (m, 5H), 5.78-5.90 (m, 1H), 5.08-5.17 (m, 2H), 4.57 (s, 2H), 3.86-3.94 (m, 1H), 3.53 (dd, J=9.6, 3.3 Hz, 1H), 3.39 (dd, J=9.6, 7.4 Hz, 1H), 2.26-2.34 (m, 3H). was maintained below −70° C Upon completion of the addition the cooling bath was removed the reaction mixture was left to stir at room temperature for 1 hour quenched by slow addition of aqueous ammonium chloride solution (200 mL) After dilution with aqueous ammonium chloride solution (1.5 L) and ethyl acetate (1.5 L), the aqueous layer was extracted with ethyl acetate (1 L) the combined organic layers were washed with aqueous ammonium chloride solution (1.5 L) dried over magnesium sulfate filtered concentrated in vacuo

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

Procedure: The product was obtained according to the method used for synthesis of (2R)-1-(benzyloxy)pent-4-en-2-ol (C1) in Preparation P1, except that 1-propenylmagnesium bromide was used in place of vinylmagnesium bromide. The product was obtained as a brown oil, which was used without further purification; by 1H NMR, this material consisted of a 1:1 mixture of geometric isomers. Yield: 140 g, 0.679 mol, 100%. 1H NMR (400 MHz, CDCl3) δ 7.28-7.42 (m, 5H), 5.39-5.67 (m, 2H), 4.57 (s, 2H), 3.80-3.92 (m, 1H), 3.48-3.57 (m, 1H), 3.35-3.43 (m, 1H), 2.36-2.50 (br m, 1H), 2.24-2.33 (m, 1H), 2.17-2.24 (m, 1H), [1.68 (br d, J=6 Hz) and 1.64 (br d, J=7 Hz), total 3H]. The product was obtained The product was obtained as a brown oil, which was used without further purification by 1H NMR, this material consisted of a 1:1 mixture of geometric isomers

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

Procedure: This reaction was carried out in two identical experiments. To a 0° C. suspension of sodium hydride (60% in mineral oil, 124.8 g, 3.12 mol) in tetrahydrofuran (1 L) was added a solution of (2R)-1-(benzyloxy)pent-4-en-2-ol (C1) (200 g, 1.04 mol) in tetrahydrofuran (500 mL). The reaction was stirred for 30 minutes at room temperature, whereupon 2-bromo-1,1-diethoxyethane (528 g, 2.68 mol) was added, and the reaction mixture was heated at reflux for 18 hours. The mixture was carefully quenched with water (2×300 mL) and the combined experiments were concentrated in vacuo. The aqueous residue was partitioned between ethyl acetate (5 L) and water (5 L). The organic layer was washed with saturated aqueous sodium chloride solution (5 L), dried, and concentrated. Purification via silica gel chromatography (Eluent: 20:1 petroleum ether/ethyl acetate) provided the product as a yellow oil. Yield: 300 g, 0.97 mol, 47%. 1H NMR (400 MHz, CDCl3) δ 7.26-7.37 (m, 5H), 5.78-5.90 (m, 1H), 5.01-5.13 (m, 2H), 4.61 (t, J=5.3 Hz, 1H), 4.55 (s, 2H), 3.48-3.74 (m, 9H), 2.30-2.36 (m, 2H), 1.22 (t, J=7.1 Hz, 3H), 1.21 (t, J=7.0 Hz, 3H). was added the reaction mixture was heated at reflux for 18 hours The mixture was carefully quenched with water (2×300 mL) the combined experiments were concentrated in vacuo The aqueous residue was partitioned between ethyl acetate (5 L) and water (5 L) The organic layer was washed with saturated aqueous sodium chloride solution (5 L) dried concentrated Purification via silica gel chromatography (Eluent: 20:1 petroleum ether/ethyl acetate)

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

Procedure: To a solution of (2R)-2-[(benzyloxy)methyl]oxirane (167 g, 1.02 mol) in tetrahydrofuran (2 L) was added copper(I) iodide (11.62 g, 61.02 mmol) at room temperature. The mixture was stirred for 5 minutes, then cooled to −78° C. A solution of vinylmagnesium bromide (1 M in tetrahydrofuran, 1.12 L, 1.12 mol) was added drop-wise over 1 hour while the reaction temperature was maintained below −70° C. Upon completion of the addition, the cooling bath was removed and the reaction mixture was left to stir at room temperature for 1 hour, then quenched by slow addition of aqueous ammonium chloride solution (200 mL). After dilution with aqueous ammonium chloride solution (1.5 L) and ethyl acetate (1.5 L), the aqueous layer was extracted with ethyl acetate (1 L) and the combined organic layers were washed with aqueous ammonium chloride solution (1.5 L), dried over magnesium sulfate, filtered, and concentrated in vacuo. Three batches of this reaction were carried out and combined to give the product as an orange oil. Yield: 600 g, 3.1 mol, quantitative. 1H NMR (400 MHz, CDCl3) δ 7.28-7.40 (m, 5H), 5.78-5.90 (m, 1H), 5.08-5.17 (m, 2H), 4.57 (s, 2H), 3.86-3.94 (m, 1H), 3.53 (dd, J=9.6, 3.3 Hz, 1H), 3.39 (dd, J=9.6, 7.4 Hz, 1H), 2.26-2.34 (m, 3H). was maintained below −70° C Upon completion of the addition the cooling bath was removed the reaction mixture was left to stir at room temperature for 1 hour quenched by slow addition of aqueous ammonium chloride solution (200 mL) After dilution with aqueous ammonium chloride solution (1.5 L) and ethyl acetate (1.5 L), the aqueous layer was extracted with ethyl acetate (1 L) the combined organic layers were washed with aqueous ammonium chloride solution (1.5 L) dried over magnesium sulfate filtered concentrated in vacuo

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

Procedure: To a solution of (2R)-2-[(benzyloxy)methyl]oxirane (167 g, 1.02 mol) in tetrahydrofuran (2 L) was added copper(I) iodide (11.62 g, 61.02 mmol) at room temperature. The mixture was stirred for 5 minutes, then cooled to −78° C. A solution of vinylmagnesium bromide (1 M in tetrahydrofuran, 1.12 L, 1.12 mol) was added drop-wise over 1 hour while the reaction temperature was maintained below −70° C. Upon completion of the addition, the cooling bath was removed and the reaction mixture was left to stir at room temperature for 1 hour, then quenched by slow addition of aqueous ammonium chloride solution (200 mL). After dilution with aqueous ammonium chloride solution (1.5 L) and ethyl acetate (1.5 L), the aqueous layer was extracted with ethyl acetate (1 L) and the combined organic layers were washed with aqueous ammonium chloride solution (1.5 L), dried over magnesium sulfate, filtered, and concentrated in vacuo. Three batches of this reaction were carried out and combined to give the product as an orange oil. Yield: 600 g, 3.1 mol, quantitative. 1H NMR (400 MHz, CDCl3) δ 7.28-7.40 (m, 5H), 5.78-5.90 (m, 1H), 5.08-5.17 (m, 2H), 4.57 (s, 2H), 3.86-3.94 (m, 1H), 3.53 (dd, J=9.6, 3.3 Hz, 1H), 3.39 (dd, J=9.6, 7.4 Hz, 1H), 2.26-2.34 (m, 3H). was maintained below −70° C Upon completion of the addition the cooling bath was removed the reaction mixture was left to stir at room temperature for 1 hour quenched by slow addition of aqueous ammonium chloride solution (200 mL) After dilution with aqueous ammonium chloride solution (1.5 L) and ethyl acetate (1.5 L), the aqueous layer was extracted with ethyl acetate (1 L) the combined organic layers were washed with aqueous ammonium chloride solution (1.5 L) dried over magnesium sulfate filtered concentrated in vacuo

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

Procedure: This reaction was carried out in two identical experiments. To a 0° C. suspension of sodium hydride (60% in mineral oil, 125 g, 3.12 mol) in tetrahydrofuran (1 L) was added a solution of C1 (200 g, 1.04 mol) in tetrahydrofuran (500 mL). The reaction was stirred for 30 minutes at room temperature, whereupon 2-bromo-1,1-diethoxyethane (528 g, 2.68 mol) was added, and the reaction mixture was heated at reflux for 18 hours. The mixture was carefully quenched with water (2×300 mL) and the combined experiments were concentrated in vacuo. The aqueous residue was partitioned between ethyl acetate (5 L) and water (5 L). The organic layer was washed with saturated aqueous sodium chloride solution (5 L), dried, and concentrated. Purification via silica gel chromatography (Eluent: 20:1 petroleum ether/ethyl acetate) provided the product as a yellow oil. Yield: 300 g, 0.97 mol, 47%. 1H NMR (400 MHz, CDCl3) δ 7.26-7.37 (m, 5H), 5.78-5.90 (m, 1H), 5.01-5.13 (m, 2H), 4.61 (t, J=5.3 Hz, 1H), 4.55 (s, 2H), 3.48-3.74 (m, 9H), 2.30-2.36 (m, 2H), 1.22 (t, J=7.1 Hz, 3H), 1.21 (t, J=7.0 Hz, 3H). was added the reaction mixture was heated at reflux for 18 hours The mixture was carefully quenched with water (2×300 mL) the combined experiments were concentrated in vacuo The aqueous residue was partitioned between ethyl acetate (5 L) and water (5 L) The organic layer was washed with saturated aqueous sodium chloride solution (5 L) dried concentrated Purification via silica gel chromatography (Eluent: 20:1 petroleum ether/ethyl acetate)

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

Procedure: To a solution of (2R)-2-[(benzyloxy)methyl]oxirane (167 g, 1.02 mol) in tetrahydrofuran (2 L) was added copper(I) iodide (11.62 g, 61.02 mmol) at room temperature. The mixture was stirred for 5 minutes, then cooled to −78° C. A solution of vinylmagnesium bromide (1 M in tetrahydrofuran, 1.12 L, 1.12 mol) was added drop-wise over 1 hour while the reaction temperature was maintained below −70° C. Upon completion of the addition, the cooling bath was removed and the reaction mixture was left to stir at room temperature for 1 hour, then quenched by slow addition of aqueous ammonium chloride solution (200 mL). After dilution with aqueous ammonium chloride solution (1.5 L) and ethyl acetate (1.5 L), the aqueous layer was extracted with ethyl acetate (1 L) and the combined organic layers were washed with aqueous ammonium chloride solution (1.5 L), dried over magnesium sulfate, filtered, and concentrated in vacuo. Three batches of this reaction were carried out and combined to give the product as an orange oil. Yield: 600 g, 3.1 mol, quantitative. 1H NMR (400 MHz, CDCl3) δ 7.28-7.40 (m, 5H), 5.78-5.90 (m, 1H), 5.08-5.17 (m, 2H), 4.57 (s, 2H), 3.86-3.94 (m, 1H), 3.53 (dd, J=9.6, 3.3 Hz, 1H), 3.39 (dd, J=9.6, 7.4 Hz, 1H), 2.26-2.34 (m, 3H). was maintained below −70° C Upon completion of the addition the cooling bath was removed the reaction mixture was left to stir at room temperature for 1 hour quenched by slow addition of aqueous ammonium chloride solution (200 mL) After dilution with aqueous ammonium chloride solution (1.5 L) and ethyl acetate (1.5 L), the aqueous layer was extracted with ethyl acetate (1 L) the combined organic layers were washed with aqueous ammonium chloride solution (1.5 L) dried over magnesium sulfate filtered concentrated in vacuo

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

Procedure: (R)-1-Benzyloxy-4-penten-2-ol (3.13 g) was dissolved in DMF (32 ml), and sodium hydride (60%, 0.91 g) was added in an ice bath. After stirring at the same temperature for 30 minutes, bromoacetaldehyde diethyl acetal (3.03 ml) was added. The mixture was heated to room temperature and stirred for two hours, and then heated to 50° C. and stirred for one hour. After cooling to room temperature, ice was added to the reaction solution. The reaction solution was extracted with ethyl acetate. The organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound. The mixture containing the recovered raw material was reacted under the same conditions. The title compound was obtained by purification by the same method (total yield: 5.00 g). stirred for two hours heated to 50° C. stirred for one hour After cooling to room temperature ice was added to the reaction solution The reaction solution was extracted with ethyl acetate The organic layer was washed with water and brine The organic layer was dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography

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

Procedure: Ether (100 ml) and copper(I) iodide (580 mg) were added to a solution of (R)-benzyl glycidyl ether (10.0 g) in THF (100 ml). The mixture was cooled to −78° C., and vinylmagnesium chloride (1.38 M, 53.0 ml) was added dropwise. The mixture was stirred overnight with gradual heating to room temperature. Ice was added to the reaction solution, and an ammonium chloride solution was further added. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with an ammonium chloride solution. The insoluble matter was removed by filtration through celite, and the solvent was evaporated under reduced pressure to obtain the title compound (12.5 g). with gradual heating to room temperature Ice was added to the reaction solution The aqueous layer was extracted with ethyl acetate the organic layer was washed with an ammonium chloride solution The insoluble matter was removed by filtration through celite the solvent was evaporated under reduced pressure

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

Procedure: (R)-1-Benzyloxy-4-penten-2-ol (3.13 g) was dissolved in DMF (32 ml), and sodium hydride (60%, 0.91 g) was added in an ice bath. After stirring at the same temperature for 30 minutes, bromoacetaldehyde diethyl acetal (3.03 ml) was added. The mixture was heated to room temperature and stirred for two hours, and then heated to 50° C. and stirred for one hour. After cooling to room temperature, ice was added to the reaction solution. The reaction solution was extracted with ethyl acetate. The organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound. The mixture containing the recovered raw material was reacted under the same conditions. The title compound was obtained by purification by the same method (total yield: 5.00 g). stirred for two hours heated to 50° C. stirred for one hour After cooling to room temperature ice was added to the reaction solution The reaction solution was extracted with ethyl acetate The organic layer was washed with water and brine The organic layer was dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography