hex-4-enoic acid

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mechanically stirred solution of 9.50 g (83.2 mmol, 1.10 equiv.) of 4-hexenoic acid (commericially available from Lancaster, Catalog #252-427-6) and 13.9 mL (10.1 g, 99.7 mmol, 1.33 equiv.) of triethylamine in 150 mL of dry THF, cooled to −78° C. under dry N2, was added 10.71 mL (10.49 g, 87.0 mmol, 1.15 equiv.) of pivaloyl chloride (Aldrich). The mixture was warmed to 0° C. for 60 min, and then recooled to −78° C. A solution of 13.4 g (75.6 mmol, 1.00 equiv) of (S)-(−)-(phenylmethyl)-2-oxazolidone (Aldrich) and 22 mg of triphenylmethane (indicator) in 150 mL of dry THF, stirred at −30° C. to −45° C. under N2, was treated dropwise with n-butyllithium (−2.5 M in hexanes) (Aldrich) until an orange color persisted (−30 mL required). The resulting solution was cooled to −78° C. and then added, via rapid cannulation, to the above stirred mixture containing the mixed anhydride. The residual lithiated oxazolidone was rinsed in with two 10-mL portions of dry THF and the resulting mixture was stirred at −78° C. for 1.5 h, and then at 0° C. for 1 h. The mixture was partitioned between CH2Cl2 and pH 7 phosphate buffer. The CH2Cl2 phase was washed with saturated aqueous NaHCO3 followed by half-saturated aqueous NaCl, dried (MgSO4), and evaporated in vacuo. The residual cream-colored solid (22.4 g) was chromatographed (Waters Prep 2000, 5.0 cm×25 cm 10μ Kromasil KR60-1OSIL-5025 column) in two batches eluting with 85:15 hexanes/EtOAc. The chromatographed product was recrystallized from hexane to yield 14.34 g (first crop, 69%) of the title compound as fine white needles. 1H NMR (300 MHz, CDCl3) δ7.37-7.20 (m, 5H, —C6H5), 5.60-5.43(m, 2H, CH═CHCH3), 4.71-4.63 (m, 1H, NCH(Ph) CH2O), 4.23-4.14 (m, 2H, NCH(Ph)CH2O), 3.295 (dd, J=13.3, 3.3 Hz, 1H, CHHC6H5), 3.11-2.90 (m, 2H, CH2C═O), 2.758 (dd, J=13.3, 9.6 Hz, 1H, CHHC6H5), 2.42-2.34 (m, 2H, CH═CHCH2), 1.67-1.65 (m, 2H, CH═CHCH3). recooled to −78° C The resulting solution was cooled to −78° C. added, via rapid cannulation, to the above stirred mixture The residual lithiated oxazolidone was rinsed in with two 10-mL portions of dry THF at 0° C. for 1 h The mixture was partitioned between CH2Cl2 and pH 7 phosphate buffer The CH2Cl2 phase was washed with saturated aqueous NaHCO3 dried (MgSO4) evaporated in vacuo The residual cream-colored solid (22.4 g) was chromatographed (Waters Prep 2000, 5.0 cm×25 cm 10μ Kromasil KR60-1OSIL-5025 column) in two batches eluting with 85:15 hexanes/EtOAc The chromatographed product was recrystallized from hexane

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mechanically stirred solution of 9.50 g (83.2 mmol, 1.10 equiv.) of 4-hexenoic acid (commericially available from Lancaster, Catalog #252-427-6) and 13.9 mL (10.1 g, 99.7 mmol, 1.33 equiv.) of triethylamine in 150 mL of dry THF, cooled to −78° C. under dry N2, was added 10.71 mL (10.49 g, 87.0 mmol, 1.15 equiv.) of pivaloyl chloride (Aldrich). The mixture was warmed to 0° C. for 60 min, and then recooled to −78° C. A solution of 13.4 g (75.6 mmol, 1.00 equiv) of (S)-(−)-(phenylmethyl)-2-oxazolidone (Aldrich) and 22 mg of triphenylmethane (indicator) in 150 mL of dry THF, stirred at −30° C. to −45° C. under N2, was treated dropwise with n-butyllithium (−2.5 M in hexanes) (Aldrich) until an orange color persisted (−30 mL required). The resulting solution was cooled to −78° C. and then added, via rapid cannulation, to the above stirred mixture containing the mixed anhydride. The residual lithiated oxazolidone was rinsed in with two 10-mL portions of dry THF and the resulting mixture was stirred at −78° C. for 1.5 h, and then at 0° C. for 1 h. The mixture was partitioned between CH2Cl2 and pH 7 phosphate buffer. The CH2Cl2 phase was washed with saturated aqueous NaHCO3 followed by half-saturated aqueous NaCl, dried (MgSO4), and evaporated in vacuo. The residual cream-colored solid (22.4 g) was chromatographed (Waters Prep 2000, 5.0 cm×25 cm 10μ Kromasil KR60-1OSIL-5025 column) in two batches eluting with 85:15 hexanes/EtOAc. The chromatographed product was recrystallized from hexane to yield 14.34 g (first crop, 69%) of the title compound as fine white needles. 1H NMR (300 MHz, CDCl3) δ7.37-7.20 (m, 5H, —C6H5), 5.60-5.43(m, 2H, CH═CHCH3), 4.71-4.63 (m, 1H, NCH(Ph) CH2O), 4.23-4.14 (m, 2H, NCH(Ph)CH2O), 3.295 (dd, J=13.3, 3.3 Hz, 1H, CHHC6H5), 3.11-2.90 (m, 2H, CH2C═O), 2.758 (dd, J=13.3, 9.6 Hz, 1H, CHHC6H5), 2.42-2.34 (m, 2H, CH═CHCH2), 1.67-1.65 (m, 2H, CH═CHCH3). recooled to −78° C The resulting solution was cooled to −78° C. added, via rapid cannulation, to the above stirred mixture The residual lithiated oxazolidone was rinsed in with two 10-mL portions of dry THF at 0° C. for 1 h The mixture was partitioned between CH2Cl2 and pH 7 phosphate buffer The CH2Cl2 phase was washed with saturated aqueous NaHCO3 dried (MgSO4) evaporated in vacuo The residual cream-colored solid (22.4 g) was chromatographed (Waters Prep 2000, 5.0 cm×25 cm 10μ Kromasil KR60-1OSIL-5025 column) in two batches eluting with 85:15 hexanes/EtOAc The chromatographed product was recrystallized from hexane

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

Procedure: A solution of methyl (E)-6-(1,3-dihydro-4-isocyanato-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate (1.0 g) in 10 ml methanol was heated to reflux for 4 hours and then evaporated to dryness. The residue was recrystallized from acetone/hexane to give 0.41 g of methyl (E)-6-(1,3-dihydro-4-methoxycarbonylamino-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate. The ester (0.35g) and 0.05 g of LiOH-H2O in 9 ml 2:1 MeoH-H2O was heated at reflux for 4hours. The mixture was acidified, extracted with ethyl acetate, and the organic layer was dried over MgSO4. The organic layer was concentrated and the residue was further purified by silica gel chromatography (eluant 60:40:2 hexaneethyl acetate:acetic acid) to give 0.21 g of (E)-6-(1,3-dihydro-4- methoxycarbonylamino-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl. 4-hexenoic acid, mp 155°-158° C. at reflux for 4hours extracted with ethyl acetate the organic layer was dried over MgSO4 The organic layer was concentrated the residue was further purified by silica gel chromatography (eluant 60:40:2 hexaneethyl acetate:acetic acid) to give 0.21 g of (E)-6-(1,3-dihydro-4- methoxycarbonylamino-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mechanically stirred solution of 9.50 g (83.2 mmol, 1.10 equiv.) of 4-hexenoic acid (commericially available from Lancaster, Catalog #252-427-6) and 13.9 mL (10.1 g, 99.7 mmol, 1.33 equiv.) of triethylamine in 150 mL of dry THF, cooled to −78° C. under dry N2, was added 10.71 mL (10.49 g, 87.0 mmol, 1.15 equiv.) of pivaloyl chloride (Aldrich). The mixture was warmed to 0° C. for 60 min, and then recooled to −78° C. A solution of 13.4 g (75.6 mmol, 1.00 equiv) of (S)-(−)-(phenylmethyl)-2-oxazolidone (Aldrich) and 22 mg of triphenylmethane (indicator) in 150 mL of dry THF, stirred at −30° C. to 45° C. under N2, was treated dropwise with n-butyllithium (˜2.5 M in hexanes) (Aldrich) until an orange color persisted (˜30 mL required). The resulting solution was cooled to −78° C. and then added, via rapid cannulation, to the above stirred mixture containing the mixed anhydride. The residual lithiated oxazolidone was rinsed in with two 10-mL portions of dry THF and the resulting mixture was stirred at −78° C. for 1.5 h, and then at 0° C. for 1 h. The mixture was partitioned between CH2Cl2 and pH 7 phosphate buffer. The CH2Cl2 phase was washed with saturated aqueous NaHCO3 followed by half-saturated aqueous NaCl, dried (MgSO4), and evaporated in vacuo. The residual cream-colored solid (22.4 g) was chromatographed (Waters Prep 2000, 5.0 cm×25 cm 10μ Kromasil KR60-10SIL-5025 column) in two batches eluting with 85:15 hexanes/EtOAc. The chromatographed product was recrystallized from hexane to yield 14.34 g (first crop, 69%) of the title compound as fine white needles. 1H NMR (300 MHz, CDCl3) a 7.37-7.20 (m, 5H, —C6H5), 5.60-5.43(m, 2H, CH═CHCH3), 4.71-4.63(m, 1H, NCH(Ph) CH20), 4.23-4.14(m, 2H, NCH(Ph)CH2O), 3.295(dd, J=13.3, 3.3 Hz, 1H, CHHC6H5), 3.11-2.90 (m, 2H, CH2C═O), 2.758 (dd, J=13.3, 9.6 Hz, 1H, CHHC6H5), 2.42-2.34 (m, 2H, CH═CHCH2), 1.67-1.65 (m, 2H, CH═CHCH3). recooled to −78° C The resulting solution was cooled to −78° C. added, via rapid cannulation, to the above stirred mixture The residual lithiated oxazolidone was rinsed in with two 10-mL portions of dry THF at 0° C. for 1 h The mixture was partitioned between CH2Cl2 and pH 7 phosphate buffer The CH2Cl2 phase was washed with saturated aqueous NaHCO3 dried (MgSO4) evaporated in vacuo The residual cream-colored solid (22.4 g) was chromatographed (Waters Prep 2000, 5.0 cm×25 cm 10μ Kromasil KR60-10SIL-5025 column) in two batches eluting with 85:15 hexanes/EtOAc The chromatographed product was recrystallized from hexane

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mechanically stirred solution of 9.50 g (83.2 mmol, 1.10 equiv.) of 4-hexenoic acid (commericially available from Lancaster, Catalog #252-427-6) and 13.9 mL (10.1 g, 99.7 mmol, 1.33 equiv.) of triethylamine in 150 mL of dry THF, cooled to −78° C. under dry N2, was added 10.71 mL (10.49 g, 87.0 mmol, 1.15 equiv.) of pivaloyl chloride (Aldrich). The mixture was warmed to 0° C. for 60 min, and then recooled to −78° C. A solution of 13.4 g (75.6 mmol, 1.00 equiv) of (S)-(−)-(phenylmethyl)-2-oxazolidone (Aldrich) and 22 mg of triphenylmethane (indicator) in 150 mL of dry THF, stirred at −30° C. to −45° C. under N2, was treated dropwise with n-butyllithium (−2.5 M in hexanes) (Aldrich) until an orange color persisted (−30 mL required). The resulting solution was cooled to −78° C. and then added, via rapid cannulation, to the above stirred mixture containing the mixed anhydride. The residual lithiated oxazolidone was rinsed in with two 10-mL portions of dry THF and the resulting mixture was stirred at −78° C. for 1.5 h, and then at 0° C. for 1 h. The mixture was partitioned between CH2Cl2 and pH 7 phosphate buffer. The CH2Cl2 phase was washed with saturated aqueous NaHCO3 followed by half-saturated aqueous NaCl, dried (MgSO4), and evaporated in vacuo. The residual cream-colored solid (22.4 g) was chromatographed (Waters Prep 2000, 5.0 cm×25 cm 10μ Kromasil KR60-1OSIL-5025 column) in two batches eluting with 85:15 hexanes/EtOAc. The chromatographed product was recrystallized from hexane to yield 14.34 g (first crop, 69%) of the title compound as fine white needles. 1H NMR (300 MHz, CDCl3) δ7.37-7.20 (m, 5H, —C6H5), 5.60-5.43(m, 2H, CH═CHCH3), 4.71-4.63 (m, 1H, NCH(Ph) CH2O), 4.23-4.14 (m, 2H, NCH(Ph)CH2O), 3.295 (dd, J=13.3, 3.3 Hz, 1H, CHHC6H5), 3.11-2.90 (m, 2H, CH2C═O), 2.758 (dd, J=13.3, 9.6 Hz, 1H, CHHC6H5), 2.42-2.34 (m, 2H, CH═CHCH2), 1.67-1.65 (m, 2H, CH═CHCH3). recooled to −78° C The resulting solution was cooled to −78° C. added, via rapid cannulation, to the above stirred mixture The residual lithiated oxazolidone was rinsed in with two 10-mL portions of dry THF at 0° C. for 1 h The mixture was partitioned between CH2Cl2 and pH 7 phosphate buffer The CH2Cl2 phase was washed with saturated aqueous NaHCO3 dried (MgSO4) evaporated in vacuo The residual cream-colored solid (22.4 g) was chromatographed (Waters Prep 2000, 5.0 cm×25 cm 10μ Kromasil KR60-1OSIL-5025 column) in two batches eluting with 85:15 hexanes/EtOAc The chromatographed product was recrystallized from hexane