methyl (3S)-3-(4-hydroxyphenyl)hex-4-ynoate

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Benzyl chloride 2.3 (28.0 g, 103 mmol) and phenol 1 (21.5 g, 98 mmol) were dissolved in acetone (150 mL) and treated with Cs2CO3 (39.9 g, 122 mmol). The reaction was stirred at 50° C. for 16 hours, filtered, and concentrated to a pale yellow oil which was chromatographed (silica gel, 33% to 66% DCM in hexanes). Eluant containing compound 2.4 was concentrated to a colorless oil (40.0 g). filtered concentrated to a pale yellow oil which was chromatographed (silica gel, 33% to 66% DCM in hexanes) Eluant containing compound 2.4 was concentrated to a colorless oil (40.0 g)

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Phenol 1.4 (23.5 g, 115 mmol) was dissolved in acetone (230 mL) and treated with KHCO3 (11.5 g, 115 mmol). After 15 minutes, methyl iodide (5 mL, 80 mmol) was added, and the reaction stirred at 40° C. for 14 hours. An additional portion of methyl iodide (3 mL, 48 mmol) was added, and heating was continued for 24 hours. Potassium salts were removed by filtration and thoroughly rinsed with acetone. The filtrate was concentrated to an oil which was filtered through a 1 cm plug of silica gel. Elution with 2.5% MeOH in DCM followed by concentration provided phenol 1 (21.5 g) as a light yellow oil. 1H NMR (500 MHz, acetone-d6) δ 8.2 (br s, 1H); 7.20 (d, 2H, J=9.5 Hz); 6.77 (d, 2H, J=9.0 Hz); 3.98 (m, 1H); 3.60 (s, 3H); 2.65 (m, 2H); 1.78 (d, 3H, J=2.5 Hz). MS ESI (pos.) m/e: 219.1 (M+H); 241.1 (M+Na). heating was continued for 24 hours Potassium salts were removed by filtration thoroughly rinsed with acetone The filtrate was concentrated to an oil which was filtered through a 1 cm plug of silica gel Elution with 2.5% MeOH in DCM followed by concentration

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Phenol 1.4 (23.5 g, 115 mmol) was dissolved in acetone (230 mL) and treated with KHCO3 (11.5 g, 115 mmol). After 15 minutes, methyl iodide (5 mL, 80 mmol) was added, and the reaction stirred at 40° C. for 14 hours. An additional portion of methyl iodide (3 mL, 48 mmol) was added, and heating was continued for 24 hours. Potassium salts were removed by filtration and thoroughly rinsed with acetone. The filtrate was concentrated to an oil which was filtered through a 1 cm plug of silica gel. Elution with 2.5% MeOH in DCM followed by concentration provided phenol 1 (21.5 g) as a light yellow oil. 1H NMR (500 MHz, acetone-d6) δ 8.2 (br s, 1H); 7.20 (d, 2H, J=9.5 Hz); 6.77 (d, 2H, J=9.0 Hz); 3.98 (m, 1H); 3.60 (s, 3H); 2.65 (m, 2H); 1.78 (d, 3H, J=2.5 Hz). MS ESI (pos.) m/e: 219.1 (M+H); 241.1 (M+Na). heating was continued for 24 hours Potassium salts were removed by filtration thoroughly rinsed with acetone The filtrate was concentrated to an oil which was filtered through a 1 cm plug of silica gel Elution with 2.5% MeOH in DCM followed by concentration

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

Procedure: 2-Methylbenzyl bromide (0.98 g, 5.3 mmol) and phenol 1 (0.97 g, 4.4 mmol) were dissolved in acetone (9 mL) and treated with Cs2CO3 (1.45 g, 4.4 mmol). The reaction was stirred at room temperature for 16 h then filtered and concentrated to an oil which was purified by radial chromatography (2 mm silica gel plate, 10% ethyl acetate in hexanes). Eluant containing compound 13.1 was concentrated to a colorless oil (1.37 g, 96%). This material was analyzed by chiral HPLC (Daicel ChiralPAK AD-H column, eluant: 0.1% TFA in 95:5 hexanes:2-propanol) and was found to have 94% ee. 1H NMR (500 MHz)(MeOH-d4) δ 7.39 (d, 1H, J=7 Hz); 7.28 (d, 2H, J=8.5 Hz); 7.25-7.15 (m, 3H); 5.05 (s, 2H); 4.02 (m, 1H); 3.64 (s, 3H); 2.68 (m, 2H); 2.36 (s, 3H); 1.80 (d, 3H, J=2.5 Hz). MS ESI (pos.) m/e: 323.0 (M+H); 245.1 (M+Na). then filtered concentrated to an oil which was purified by radial chromatography (2 mm silica gel plate, 10% ethyl acetate in hexanes) Eluant containing compound 13.1 was concentrated to a colorless oil (1.37 g, 96%)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Benzyl chloride 2.3 (28.0 g, 103 mmol) and phenol 1 (21.5 g, 98 mmol) were dissolved in acetone (150 mL) and treated with Cs2CO3 (39.9 g, 122 mmol). The reaction was stirred at 50° C. for 16 h then filtered and concentrated to an pale yellow oil which was purified by column chromatography (silica gel, 33% to 66% dichloromethane in hexanes). Eluant containing compound 2.4 was concentrated to a colorless oil (40.0 g, 92%). then filtered concentrated to an pale yellow oil which was purified by column chromatography (silica gel, 33% to 66% dichloromethane in hexanes) Eluant containing compound 2.4 was concentrated to a colorless oil (40.0 g, 92%)

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Phenol 1.4 (23.5 g, 115 mmol) was dissolved in acetone (230 mL) and treated with KHCO3 (11.5 g, 115 mmol). After 15 minutes, methyl iodide (5 mL, 80 mmol) was added, and the reaction stirred at 40° C. for 14 h. An additional portion of methyl iodide (3 mL, 48 mmol) was added and heating was continued for 24 h. Potassium salts were removed by filtration and thoroughly rinsed with acetone. The filtrate was concentrated to an oil which was purified by filtration through a 1 cm plug of silica gel. Elution with 2.5% MeOH in dichloromethane followed by concentration provided phenol 1 (21.5 g, 85%) as a light yellow oil. 1H NMR (500 MHz)(acetone-d6) δ 8.2 (br s, 1H); 7.20 (d, 2H, J=9.5 Hz); 6.77 (d, 2H, J=9.0 Hz); 3.98 (m, 1H); 3.60 (s, 3H); 2.65 (m, 2H); 1.78 (d, 3H, J=2.5 Hz). MS ESI (pos.) m/e: 219.1 (M+H); 241.1 (M+Na). heating was continued for 24 h Potassium salts were removed by filtration thoroughly rinsed with acetone The filtrate was concentrated to an oil which was purified by filtration through a 1 cm plug of silica gel Elution with 2.5% MeOH in dichloromethane followed by concentration

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

Procedure: 2-Methylbenzyl bromide (0.98 g, 5.3 mmol) and phenol 1 (0.97 g, 4.4 mmol) were dissolved in acetone (9 mL) and treated with Cs2CO3 (1.45 g, 4.4 mmol). The reaction was stirred at room temperature for 16 h then filtered and concentrated to an oil which was purified by radial chromatography (2 mm silica gel plate, 10% ethyl acetate in hexanes). Eluant containing compound 13.1 was concentrated to a colorless oil (1.37 g, 96%). This material was analyzed by chiral HPLC (Daicel ChiralPAK AD-H column, eluant: 0.1% TFA in 95:5 hexanes:2-propanol) and was found to have 94% ee. 1H NMR(500 MHz)(MeOH-d4) δ 7.39 (d, 1H, J=7 Hz); 7.28 (d, 2H, J=8.5 Hz); 7.25-7.15 (m, 3H); 5.05 (s, 2H); 4.02 (m, 1H); 3.64 (s, 3H); 2.68 (m, 2H); 2.36 (s, 3H); 1.80 (d, 3H, J=2.5 Hz). MS ESI (pos.) m/e: 323.0 (M+H); 245.1 (M+Na). then filtered concentrated to an oil which was purified by radial chromatography (2 mm silica gel plate, 10% ethyl acetate in hexanes) Eluant containing compound 13.1 was concentrated to a colorless oil (1.37 g, 96%)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Benzyl chloride 2.3 (28.0 g, 103 mmol) and phenol 1 (21.5 g, 98 mmol) were dissolved in acetone (150 mL) and treated with Cs2CO3 (39.9 g, 122 mmol). The reaction was stirred at 50° C. for 16 h then filtered and concentrated to an pale yellow oil which was purified by column chromatography (silica gel, 33% to 66% dichloromethane in hexanes). Eluant containing compound 2.4 was concentrated to a colorless oil (40.0 g, 92%). then filtered concentrated to an pale yellow oil which was purified by column chromatography (silica gel, 33% to 66% dichloromethane in hexanes) Eluant containing compound 2.4 was concentrated to a colorless oil (40.0 g, 92%)

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Phenol 1.4 (23.5 g, 115 mmol) was dissolved in acetone (230 mL) and treated with KHCO3 (11.5 g, 115 mmol). After 15 minutes, methyl iodide (5 mL, 80 mmol) was added, and the reaction stirred at 40° C. for 14 h. An additional portion of methyl iodide (3 mL, 48 mmol) was added and heating was continued for 24 h. Potassium salts were removed by filtration and thoroughly rinsed with acetone. The filtrate was concentrated to an oil which was purified by filtration through a 1 cm plug of silica gel. Elution with 2.5% MeOH in dichloromethane followed by concentration provided phenol 1 (21.5 g, 85%) as a light yellow oil. 1H NMR(500 MHz)(acetone-d6) δ 8.2 (br s, 1H); 7.20 (d, 2H, J=9.5 Hz); 6.77 (d, 2H, J=9.0 Hz); 3.98 (m, 1H); 3.60 (s, 3H); 2.65 (m, 2H); 1.78 (d, 3H, J=2.5 Hz). MS ESI (pos.) m/e: 219.1 (M+H); 241.1 (M+Na). heating was continued for 24 h Potassium salts were removed by filtration thoroughly rinsed with acetone The filtrate was concentrated to an oil which was purified by filtration through a 1 cm plug of silica gel Elution with 2.5% MeOH in dichloromethane followed by concentration