[(2S)-oxiran-2-yl]methyl butanoate

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

Procedure: Using the (R,R)-(salen)Co(II) precatalyst of 1 (91 mg, 0.15 mmol, 0.005equiv), (+/−)-glycidyl butyrate (4.32 g, 30.0 mmol), AcOH (32 mL, 0.6 mnmol, 0.02 equiv), 0.3 mL THF, and H2O (297 mL, 16.5 mmol, 0.55 equiv) and a procedure analogous to the one outlined for 5b, (S)-glycidyl butyrate 5d (1.90 g, 13.2 mmol, 44%) was obtained as a clear oil by vacuum distillation of the reaction mixture (30° C., 0.5 torr). The product was determined to be >99% ee by conversion to and analysis of the 2-napthylsulfide (obtained by ring opening with 2-napthalenethiol in methanol using 1 equiv TEA at 0° C.; Chiralcel OD, 97:3 hexanes:EtOH, 1 mL/min, 260 mn).

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

Procedure: A mixture of 3-fluoro-4-methyl-aniline (commercial; 1.25 g, 10 mmol), sat. aq. NaHCO3 (10 mL) and acetone (10 mL) was treated dropwise with benzyl chloroformate (1.70 g, 1.41 mL, 1 eq.). After CO2 evolution ceased, the mixture was partitioned between EA and sat. aq. NaHCO3, the org. layer was dried over MgSO4 and concentrated under reduced pressure. The resulting benzyl carbamate was dissolved in THF (50 mL) and cooled under argon to −78° C. n-BuLi (2.5M in Hex, 6.45 mL, 1.1 eq.) was added dropwise, and the resulting solution was stirred for 1 h at that temperature. The reaction was then allowed to warm to −15° C. at which (S)-glycidyl butyrate (1.69 mL, 1.1 eq.) was added dropwise. The mixture was stirred at rt overnight. A tip of a spatula of Cs2CO3 was added, and the mixture was stirred at rt for 3 h. NH4Cl and EA were added and the phases were separated. The aq. phase was extracted once more with EA and the combined org. extracts were washed several times with sat. aq. NH4Cl, then with brine, dried over Na2SO4 and concentrated. The orange solid obtained was triturated with EA to afford the title intermediate as a pale yellow solid (1.18 g, 53% yield). the mixture was partitioned between EA and sat. aq. NaHCO3 layer was dried over MgSO4 concentrated under reduced pressure The resulting benzyl carbamate was dissolved in THF (50 mL) was added dropwise was added dropwise The mixture was stirred at rt overnight the mixture was stirred at rt for 3 h the phases were separated The aq. phase was extracted once more with EA extracts were washed several times with sat. aq. NH4Cl with brine, dried over Na2SO4 concentrated The orange solid obtained was triturated with EA

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

Procedure: A mixture of 3-fluoro-4-methyl-aniline (commercial; 1.25 g, 10 mmol), sat. aq. NaHCO3 (10 mL) and acetone (10 mL) was treated dropwise with benzyl chloroformate (1.70 g, 1.41 mL, 1 eq.). After CO2 evolution ceased, the mixture was partitioned between EA and sat. aq. NaHCO3, the org. layer was dried over MgSO4 and concentrated under reduced pressure. The resulting benzyl carbamate was dissolved in THF (50 mL) and cooled under argon to −78° C. n-BuLi (2.5M in Hex, 6.45 mL, 1.1 eq.) was added dropwise, and the resulting solution was stirred for 1 h at that temperature. The reaction was then allowed to warm to −15° C. at which (S)-glycidyl butyrate (1.69 mL, 1.1 eq.) was added dropwise. The mixture was stirred at rt overnight. A tip of a spatula of Cs2CO3 was added, and the mixture was stirred at rt for 3 h. NH4Cl and EA were added and the phases were separated. The aq. phase was extracted once more with EA and the combined org. extracts were washed several times with sat. aq. NH4Cl, then with brine, dried over Na2SO4 and concentrated. The orange solid obtained was triturated with EA to afford the title intermediate as a pale yellow solid (1.18 g, 53% yield). the mixture was partitioned between EA and sat. aq. NaHCO3 layer was dried over MgSO4 concentrated under reduced pressure The resulting benzyl carbamate was dissolved in THF (50 mL) was added dropwise was added dropwise The mixture was stirred at rt overnight the mixture was stirred at rt for 3 h the phases were separated The aq. phase was extracted once more with EA extracts were washed several times with sat. aq. NH4Cl with brine, dried over Na2SO4 concentrated The orange solid obtained was triturated with EA

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

Procedure: A solution of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-carbamic acid benzyl ester (13.0 g, 45.6 mmol) in THF (220 mL) was cooled to −78° C. before the dropwise addition of n-BuLi (29.5 mL of a 2.3M solution in Hex, 1.1 eq.). The mixture was stirred at −78° C. for 1 h and then warmed to −15° C. and treated dropwise with (S)-glycidyl butyrate (7.37 g, 1.1 eq.). The mixture was stirred at rt overnight. Cs2CO3 (tip of a spatula) was added and the mixture heated at 40° C. until complete conversion. The mixture was diluted with EA and washed with a sat. aq. NH4Cl and water. The org. layer was dried over MgSO4 and concentrated. The residue was purified by CC (Hex/EA 2:1, 1:1) to afford the title intermediate as a grey solid (7.04 g, 62% yield). warmed to −15° C. The mixture was stirred at rt overnight the mixture heated at 40° C. until complete conversion washed with a sat. aq. NH4Cl and water layer was dried over MgSO4 concentrated The residue was purified by CC (Hex/EA 2:1, 1:1)

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

Procedure: A solution of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-carbamic acid benzyl ester (13.0 g, 45.6 mmol) in THF (220 mL) was cooled to −78° C. before the dropwise addition of n-BuLi (29.5 mL of a 2.3M solution in Hex, 1.1 eq.). The mixture was stirred at −78° C. for 1 h and then warmed to −15° C. and treated dropwise with (S)-glycidyl butyrate (7.37 g, 1.1 eq.). The mixture was stirred at rt overnight. Cs2CO3 (tip of a spatula) was added and the mixture heated at 40° C. until complete conversion. The mixture was diluted with EA and washed with a sat. aq. NH4Cl and water. The org. layer was dried over MgSO4 and concentrated. The residue was purified by CC (Hex/EA 2:1, 1:1) to afford the title intermediate as a grey solid (7.04 g, 62% yield). warmed to −15° C. The mixture was stirred at rt overnight the mixture heated at 40° C. until complete conversion washed with a sat. aq. NH4Cl and water layer was dried over MgSO4 concentrated The residue was purified by CC (Hex/EA 2:1, 1:1)

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

Procedure: Using the (R,R)-(salen)Co(II) precatalyst of 1 (91 mg, 0.15 mmol, 0.005equiv), (+/−)-glycidyl butyrate (4.32 g, 30.0 mmol), AcOH (32 mL, 0.6 mnmol, 0.02 equiv), 0.3 mL THF, and H2O (297 mL, 16.5 mmol, 0.55 equiv) and a procedure analogous to the one outlined for 5b, (S)-glycidyl butyrate 5d (1.90 g, 13.2 mmol, 44%) was obtained as a clear oil by vacuum distillation of the reaction mixture (30° C., 0.5 torr). The product was determined to be >99% ee by conversion to and analysis of the 2-napthylsulfide (obtained by ring opening with 2-napthalenethiol in methanol using 1 equiv TEA at 0° C.; Chiralcel OD, 97:3 hexanes:EtOH, 1 mL/min, 260 mn).

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

Procedure: Using the (R,R)-(salen)Co(II) precatalyst of 1 (91 mg, 0.15 mmol, 0.005equiv), (+/−)-glycidyl butyrate (4.32 g, 30.0 mmol), AcOH (32 mL, 0.6 mnmol, 0.02 equiv), 0.3 mL THF, and H2O (297 mL, 16.5 mmol, 0.55 equiv) and a procedure analogous to the one outlined for 5b, (S)-glycidyl butyrate 5d (1.90 g, 13.2 mmol, 44%) was obtained as a clear oil by vacuum distillation of the reaction mixture (30° C., 0.5 torr). The product was determined to be >99% ee by conversion to and analysis of the 2-napthylsulfide (obtained by ring opening with 2-napthalenethiol in methanol using 1 equiv TEA at 0° C.; Chiralcel OD, 97:3 hexanes:EtOH, 1 mL/min, 260 mn).

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

Procedure: In Scheme 4, aniline (62) and benzyl chloroformate (63) are reacted in the presence of NaHCO3 and acetone:water (2:1) to generate benzyl N-phenylcarbamate (64), which when reacted with Cs2CO3 and (S)-(+)-glycidyl butyrate (65), in DMF solution gives the 5-(hydroxymethyl)-3-phenyloxazolidin-2-one (66), which upon treatment with NaIO4, RuCl3, H2O generates (67).

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

Procedure: A mixture of 3-fluoro-4-methyl-aniline (commercial; 1.25 g, 10 mmol), sat. aq. NaHCO3 (10 mL) and acetone (10 mL) was treated dropwise with benzyl chloroformate (1.70 g, 1.41 mL, 1 eq.). After CO2 evolution ceased, the mixture was partitioned between EA and sat. aq. NaHCO3, the org. layer was dried over MgSO4 and concentrated under reduced pressure. The resulting benzyl carbamate was dissolved in THF (50 mL) and cooled under argon to −78° C. n-BuLi (2.5M in Hex, 6.45 mL, 1.1 eq.) was added dropwise, and the resulting solution was stirred for 1 h at that temperature. The reaction was then allowed to warm to −15° C. at which (S)-glycidyl butyrate (1.69 mL, 1.1 eq.) was added dropwise. The mixture was stirred at rt overnight. A tip of a spatula of Cs2CO3 was added, and the mixture was stirred at rt for 3 h. NH4Cl and EA were added and the phases were separated. The aq. phase was extracted once more with EA and the combined org. extracts were washed several times with sat. aq. NH4Cl, then with brine, dried over Na2SO4 and concentrated. The orange solid obtained was triturated with EA to afford the title intermediate as a pale yellow solid (1.18 g, 53% yield). the mixture was partitioned between EA and sat. aq. NaHCO3 layer was dried over MgSO4 concentrated under reduced pressure The resulting benzyl carbamate was dissolved in THF (50 mL) was added dropwise was added dropwise The mixture was stirred at rt overnight the mixture was stirred at rt for 3 h the phases were separated The aq. phase was extracted once more with EA extracts were washed several times with sat. aq. NH4Cl with brine, dried over Na2SO4 concentrated The orange solid obtained was triturated with EA

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

Procedure: A solution of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-carbamic acid benzyl ester (13.0 g, 45.6 mmol) in THF (220 mL) was cooled to −78° C. before the dropwise addition of n-BuLi (29.5 mL of a 2.3M solution in Hex, 1.1 eq.). The mixture was stirred at −78° C. for 1 h and then warmed to −15° C. and treated dropwise with (S)-glycidyl butyrate (7.37 g, 1.1 eq.). The mixture was stirred at rt overnight. Cs2CO3 (tip of a spatula) was added and the mixture heated at 40° C. until complete conversion. The mixture was diluted with EA and washed with a sat. aq. NH4Cl and water. The org. layer was dried over MgSO4 and concentrated. The residue was purified by CC (Hex/EA 2:1, 1:1) to afford the title intermediate as a grey solid (7.04 g, 62% yield). warmed to −15° C. The mixture was stirred at rt overnight the mixture heated at 40° C. until complete conversion washed with a sat. aq. NH4Cl and water layer was dried over MgSO4 concentrated The residue was purified by CC (Hex/EA 2:1, 1:1)

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

Procedure: A mixture of 3-fluoro-4-methyl-aniline (commercial; 1.25 g, 10 mmol), sat. aq. NaHCO3 (10 mL) and acetone (10 mL) was treated dropwise with benzyl chloroformate (1.70 g, 1.41 mL, 1 eq.). After CO2 evolution ceased, the mixture was partitioned between EA and sat. aq. NaHCO3, the org. layer was dried over MgSO4 and concentrated under reduced pressure. The resulting benzyl carbamate was dissolved in THF (50 mL) and cooled under argon to −78° C. n-BuLi (2.5M in hexanes, 6.45 mL, 1.1 eq.) was added dropwise, and the resulting solution was stirred for 1 h at that temperature. The reaction was then allowed to warm to −15° C. at which (S)-glycidyl butyrate (1.69 mL, 1.1 eq.) was added dropwise. The mixture was stirred at rt overnight. A tip of a spatula of Cs2CO3 was added, and the mixture was stirred at rt for 3 h. NH4Cl and EA were added and the phases were separated. The aq. phase was extracted once more with EA and the combined org. extracts were washed several times with sat. aq. NH4Cl, then with brine, dried over Na2SO4 and concentrated. The resulting orange solid was triturated with EA to afford the title intermediate as a pale yellow solid (1.18 g, 53% yield). the mixture was partitioned between EA and sat. aq. NaHCO3 layer was dried over MgSO4 concentrated under reduced pressure The resulting benzyl carbamate was dissolved in THF (50 mL) was added dropwise was added dropwise The mixture was stirred at rt overnight the mixture was stirred at rt for 3 h the phases were separated The aq. phase was extracted once more with EA extracts were washed several times with sat. aq. NH4Cl with brine, dried over Na2SO4 concentrated The resulting orange solid was triturated with EA

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

Procedure: A solution of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-carbamic acid benzyl ester (13.0 g, 45.6 mmol) in THF (220 mL) was cooled to −78° C. before the drop wise addition of n-BuLi (29.5 mL of a 2.36M solution in hexanes, 1.1 eq). The mixture was stirred at −78° C. for 1 h and then warmed to −15° C. At this temperature (S)-glycidyl butyrate (7.37 g, 1.1 eq) was added dropwise. The mixture was stirred at rt overnight. Cs2CO3 (tip of a spatula) was added and the mixture heated at 40° C. until complete conversion. The mixture was diluted with EA and washed with a sat. aq. NH4Cl and water. The org. layer was dried over MgSO4 and concentrated. The residue was purified by CC (Hex/EA 2:1, 1:1) to afford the title intermediate as a grey solid (7.04 g, 62% yield). warmed to −15° C The mixture was stirred at rt overnight the mixture heated at 40° C. until complete conversion washed with a sat. aq. NH4Cl and water layer was dried over MgSO4 concentrated The residue was purified by CC (Hex/EA 2:1, 1:1)