dibutylboranyl trifluoromethanesulfonate

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

Procedure: 1.8 g (7.21 mmol) (S)-4-Benzyl-3-methoxyacetyl-oxazolidin-2-one (for the preparation of (S)-4-benzyl-3-methoxyacetyl-oxazolidin-2-one see: D. Hunziker, N. Wu, K. Kenoshita, D. E. Cane, C. Khosla, Tetrahedron Lett. 1999, 40, 635-638) were dissolved under an argon atmosphere in 10 ml CH2Cl2 and treated with 1.44 ml (8.42 mmol) Hünig's base. After cooling to −78° C., nBu2BOTf was added slowly (7.21 ml of 1M solution in CH2Cl2) and enolborinate formation allowed to proceed for 0.25 hours at −78° C. and for 1 hour at 0° C. After recooling to −78° C., a solution of 2.8 g (6 mmol) of 2-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde in 10 ml CH2Cl2 was added via dropping funnel during 90 minutes and the mixture kept for 95 minutes at −78° C. and for one hour at 0° C. Pouring onto crashed ice, twofold extraction with AcOEt, washing with brine and water, drying over magnesium sulfate, and evaporation of the solvents, followed by chromatography (silica gel, heptane/AcOEt) left finally 2.905 g (67%) of the title compound as a yellow oil. According to 1H-NMR spectroscopy, one of the four isomers is strongly predominating. The configuration was tentatively assigned as 2S,3R according to D. Haigh et al., Tetrahedron: Asymmetry 1999, 10, 1353-1367. After recooling to −78° C. during 90 minutes the mixture kept for 95 minutes at −78° C. and for one hour at 0° C Pouring ice, twofold extraction with AcOEt washing with brine and water drying over magnesium sulfate, and evaporation of the solvents left finally 2.905 g (67%) of the title compound as a yellow oil

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

Procedure: Step A (5): 2R,4R)-tert-butyl 2-((1S,2S)-2-(3,5-difluorobenzyl)-3-((S)-4-benzyl-2-oxooxazolidin-3-yl)-1-hydroxy-3-oxopropyl)-4-(allyloxy)pyrrolidine-1-carboxylate. To a solution of (S)-4-benzyl-3-(3-(3,5-difluorophenyl)propanoyl)oxazolidin-2-one (Preparation B, 1.47 g, 4.27 mmol) in CH2Cl2 (15 ml) at −78° C. was added Bu2BOTf (5.12 ml, 5.12 mmol, 1M in CH2Cl2) and Hunig's base (1.12 ml, 6.41 mmol). The resulting mixture was brought to 0° C. and stirred for 30 min. The mixture was again cooled to −78° C. and a solution of (2R,4R)-tert-butyl 4-(allyloxy)-2-formylpyrrolidine-1-carboxylate (Step A (4), 1.09 g, 4.27 mmol) in CH2Cl2 (10 ml) was added dropwise. When the addition was complete, the mixture was stirred at −78° C. for 5 min., then was allowed to warm to rt. After stirring at rt for 4 h. the mixture was concentrated in vacuo. Flash chromatography (silica gel, 0-75% ethyl acetate/hexane) gave 1.22 g (48%) of (2R,4R)-tert-butyl 2-((1S,2S)-2-(3,5-difluorobenzyl)-3-((S)-4-benzyl-2-oxooxazolidin-3-yl)-1-hydroxy-3-oxopropyl)-4-(allyloxy)pyrrolidine-1-carboxylate as a slightly yellow oil: 1H NMR (CDCl3, 300 MHz) δ 1.49 (9H, s), 2.03-2.22 (2H, m), 2.31 (1H, d, J=12 Hz), 2.98 (1H, dd, J=3, 15 Hz), 3.07 (1H, t, J=12 Hz), 3.42-3.57 (3H, m), 3.97-4.11 (8H, m), 4.57 (2H, brd s), 5.17-5.30 (2H, m), 5.81-5.94 (1H, m), 6.61 (1H, t, J=9 Hz), 6.90 (2H, brd s), 7.00 (2H, brd s), 7.26 (3H, m). HPLC retention time: 2.04 min (method A). MS (ESI) (M+H)+ 601.37. was brought to 0° C. When the addition the mixture was stirred at −78° C. for 5 min. to warm to rt After stirring at rt for 4 h. the mixture was concentrated in vacuo

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

Procedure: Step A (5): 2R,4R)-tert-butyl 2-((1S,2S)-2-(3,5-difluorobenzyl)-3-((S)-4-benzyl-2-oxooxazolidin-3-yl)-1-hydroxy-3-oxopropyl)-4-(allyloxy)pyrrolidine-1-carboxylate. To a solution of (S)-4-benzyl-3-(3-(3,5-difluorophenyl)propanoyl)oxazolidin-2-one (Preparation B, 1.47 g, 4.27 mmol) in CH2Cl2 (15 ml) at −78° C. was added Bu2BOTf (5.12 ml, 5.12 mmol, 1M in CH2Cl2) and Hunig's base (1.12 ml, 6.41 mmol). The resulting mixture was brought to 0° C. and stirred for 30 min. The mixture was again cooled to −78° C. and a solution of (2R,4R)-tert-butyl 4-(allyloxy)-2-formylpyrrolidine-1-carboxylate (Step A (4), 1.09 g, 4.27 mmol) in CH2Cl2 (10 ml) was added dropwise. When the addition was complete, the mixture was stirred at −78° C. for 5 min., then was allowed to warm to rt. After stirring at rt for 4 h. the mixture was concentrated in vacuo. Flash chromatography (silica gel, 0-75% ethyl acetate/hexane) gave 1.22 g (48%) of (2R,4R)-tert-butyl 2-((1S,2S)-2-(3,5-difluorobenzyl)-3-((S)-4-benzyl-2-oxooxazolidin-3-yl)-1-hydroxy-3-oxopropyl)-4-(allyloxy)pyrrolidine-1-carboxylate as a slightly yellow oil: 1H NMR (CDCl3, 300 MHz) δ 1.49 (9H, s), 2.03-2.22 (2H, m), 2.31 (1H, d, J=12 Hz), 2.98 (1H, dd, J=3, 15 Hz), 3.07 (1H, t, J=12 Hz), 3.42-3.57 (3H, m), 3.97-4.11 (8H, m), 4.57 (2H, brd s), 5.17-5.30 (2H, m), 5.81-5.94 (1H, m), 6.61 (1H, t, J=9 Hz), 6.90 (2H, brd s), 7.00 (2H, brd s), 7.26 (3H, m). HPLC retention time: 2.04 min (method A). MS (ESI) (M+H)+ 601.37. was brought to 0° C. When the addition the mixture was stirred at −78° C. for 5 min. to warm to rt After stirring at rt for 4 h. the mixture was concentrated in vacuo

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

Procedure: A solution of (R)-4-benzyl-3-propionyl-2-oxazolidinone (2.18 g, 9.34 mmol) and methylene chloride (15 mL) is cooled to −20° C. (n-Bu)2BOTf (1.0 M in DCM, 8.7 mL, 8.7 mmol) is introduced dropwise. The reaction is allowed to warm to 0° C. NEt3 (1.15 9, 11.34 mmol) is added and the mixture is stirred at 0° C. for 1 h, then cooled to −78° C. A solution of (2R,3S,4S,5Z)-3-[(4-methoxyphenyl)methoxy]-2,4-dimethyl-5,7-octadienal (1.95 g, 6.77 mmol) in DCM (10 mL) is added dropwise at −70° C. for 10 min. After 1 h at −74° C., the mixture is warmed to 0° C. The reaction is quenched with pH 7 buffer (15 mL). The mixture is slowly treated with a solution of 30% H2O2 in MeOH (1:2, 15 mL) at 0° C., stirred for 40 min at room temperature, and concentrated. The residue is extracted with ethyl acetate (3×100 mL). The combined organic phase is washed with saturated aqueous NaHCO3, brine, and concentrated. Flash chromatography gives the desired compound (3.4 g, 96.4%) as a clear oil. is introduced dropwise cooled to −78° C After 1 h at −74° C. the mixture is warmed to 0° C The reaction is quenched with pH 7 buffer (15 mL) The mixture is slowly treated with a solution of 30% H2O2 in MeOH (1:2, 15 mL) at 0° C. stirred for 40 min at room temperature concentrated The residue is extracted with ethyl acetate (3×100 mL) The combined organic phase is washed with saturated aqueous NaHCO3, brine concentrated

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

Procedure: A solution of (R)-4-benzyl-3-propionyl-2-oxazolidinone (2.18 g, 9.34 mmol) and methylene chloride (15 mL) is cooled to −20° C. (n-Bu)2BOTf (1.0 M in DCM, 8.7 mL, 8.7 mmol) is introduced dropwise. The reaction is allowed to warm to 0° C. NEt3 (1.15 9, 11.34 mmol) is added and the mixture is stirred at 0° C. for 1 h, then cooled to −78° C. A solution of (2R,3S,4S,5Z)-3-[(4-methoxyphenyl)methoxy]-2,4-dimethyl-5,7-octadienal (1.95 g, 6.77 mmol) in DCM (10 mL) is added dropwise at −70° C. for 10 min. After 1 h at −74° C., the mixture is warmed to 0° C. The reaction is quenched with pH 7 buffer (15 mL). The mixture is slowly treated with a solution of 30% H2O2 in MeOH (1:2, 15 mL) at 0° C., stirred for 40 min at room temperature, and concentrated. The residue is extracted with ethyl acetate (3×100 mL). The combined organic phase is washed with saturated aqueous NaHCO3, brine, and concentrated. Flash chromatography gives the desired compound (3.4 g, 96.4%) as a clear oil. is introduced dropwise cooled to −78° C After 1 h at −74° C. the mixture is warmed to 0° C The reaction is quenched with pH 7 buffer (15 mL) The mixture is slowly treated with a solution of 30% H2O2 in MeOH (1:2, 15 mL) at 0° C. stirred for 40 min at room temperature concentrated The residue is extracted with ethyl acetate (3×100 mL) The combined organic phase is washed with saturated aqueous NaHCO3, brine concentrated

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

Procedure: To a solution of (S)-4-benzyl-3-(3-(3,5-difluorophenyl)propanoyl)oxazolidin-2-one (preparation D, 1.3 g, 3.77 mmol) in CH2Cl2 (50 mL) at −78° C. was added Bu2BOTf (4.90 ml, 4.90 mmol, 1M in CH2Cl2) and Hunig's base (972 mg, 7.54 mmol). The resulting mixture was brought up to 0° C. and stirred for 20 min. The mixture was cooled back to −78° C. and a solution of (R)-tert-butyl 3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (Step A (3), 1.10 g, 4.20 mmol) in CH2Cl2 (50 mL) was added dropwise. When the addition was complete, the mixture was allowed to warm to rt. After stirring at rt for 1 h, MeOH was added and the mixture was concentrated in vacuo. The crude mixture was purified by silica gel Flash chromatography to give 1.78 g (78% yield) of the title compound. MS (ESI)(M+H)+ 607.20. was brought up to 0° C. When the addition to warm to rt After stirring at rt for 1 h the mixture was concentrated in vacuo The crude mixture was purified by silica gel Flash chromatography

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

Procedure: In analogy to the procedures described in examples 11 a] to 11 c], 2-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde (prepared from 4-hydroxy-2-methoxy-benzaldehyde and methanesulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester in analogy to the procedure described in example 114 b]) was reacted with (S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one and nBu2BOTf to yield (S)-4-benzyl-3-((2S,3R)-2-ethoxy-3-hydroxy-3-{2-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one (according to NMR, one of the four isomers is strongly predominating; the configuration was tentatively assigned as 2S, 3R according to Tetrahedron Asymmetry 1999, 1353). Reduction of (S)-4-benzyl-3-((2S,3R)-2-ethoxy-3-hydroxy-3-{2-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one with triethylsilane in trifluoroacetic acid then gave (S)-4-benzyl-3-((2S)-2-ethoxy-3-{2-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one. The (S)-4-benzyl-3-((2S)-2-ethoxy-3-{2-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one was subsequently saponified with 1N NaOH in THF to yield (2S)-2-ethoxy-3-{2-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid as colorless solid.

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

Procedure: In analogy to the procedures described in examples 11 a] to 11 c], 2-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde (prepared from 4-hydroxy-2-methoxy-benzaldehyde and methanesulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester in analogy to the procedure described in example 114 b]) was reacted with (S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one and nBu2BOTf to yield (S)-4-benzyl-3-((2S,3R)-2-ethoxy-3-hydroxy-3-{2-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one (according to NMR, one of the four isomers is strongly predominating; the configuration was tentatively assigned as 2S, 3R according to Tetrahedron Asymmetry 1999, 1353). Reduction of (S)-4-benzyl-3-((2S,3R)-2-ethoxy-3-hydroxy-3-{2-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one with triethylsilane in trifluoroacetic acid then gave (S)-4-benzyl-3-((2S)-2-ethoxy-3-{2-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one. The (S)-4-benzyl-3-((2S)-2-ethoxy-3-{2-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one was subsequently saponified with 1N NaOH in THF to yield (2S)-2-ethoxy-3-{2-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid as colorless solid.

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

Procedure: In analogy to the procedures described in examples 11 a] to 11 c], 3-methoxy-4-[2-(5-methyl2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde (prepared from 4-hydroxy-3-methoxy-benzaldehyde and methanesulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester in analogy to the procedure described in example 114 b]) was reacted with (S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one and nBu2BOTf to yield (S)-4-benzyl-3-((2S,3R) -2-ethoxy-3-hydroxy-3-{3-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one (according to NMR, one of the four isomers is strongly predominating; the configuration was tentatively assigned as 2S, 3R according to Tetrahedron Asymmetry 1999, 1353). Reduction of (S)-4-benzyl-3-((2S,3R)-2-ethoxy-3-hydroxy-3-{3-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one with triethylsilane in trifluoroacetic acid then gave (S)-4-benzyl-3-((2S)-2-ethoxy-3-{3-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one. The (S)-4-benzyl-3-((2S)-2-ethoxy-3-{3-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one was subsequently saponified with 1N NaOH in THF to yield (2S)-2-ethoxy-3-{3-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid as colorless solid. The enantiomeric excess was judged according to chiral HPLC (Chiralcel-OJ) to be 98.7%.

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

Procedure: In analogy to the procedures described in examples 11 a] to 11 c], 3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde (example 117) was reacted with (S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one and nBu2BOTf to yield (S)-4-benzyl-3-((2S,3R)-3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-ethoxy-3-hydroxy-propionyl)-oxazolidin-2-one (according to NMR, one of the four isomers is strongly predominating; the configuration was tentatively assigned as 2S, 3R according to Tetrahedron Asymmetry 1999, 1353). Reduction of (S)-4-benzyl-3-((2S,3R)-3-}3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-ethoxy-3-hydroxy-propionyl)-oxazolidin-2-one with triethylsilane in trifluoroacetic acid then gave (S)-4-benzyl-3-((2S)-3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-ethoxy-propionyl)-oxazolidin-2-one. The (S)-4-benzyl-3-((2S)-3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-ethoxy-propionyl)-oxazolidin-2-one was subsequently saponified with 1N NaOH in THF to yield (2S)-3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-ethoxy-propionic acid as colorless solid. The enantiomeric excess was judged according to chiral HPLC (Chiralpak-AD) to be 98.8%.

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

Procedure: In analogy to the procedures described in examples 11 a] to 11 c], 3-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde (example 114 b]) was reacted with (S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one and nBu2BOTf to yield (S)-4-benzyl-3-((2S,3R) -2-ethoxy-3-hydroxy-3-{3-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one (according to NMR, one of the four isomers is strongly predominating; the configuration was tentatively assigned as 2S, 3R according to Tetrahedron Asymmetry 1999, 1353). Reduction of (S)-4-benzyl-3-((2S,3R)-2-ethoxy-3-hydroxy-3-{3-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one with triethylsilane in trifluoroacetic acid then gave (S)-4-benzyl-3-((2S)-2-ethoxy-3-{3-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one. The (S)-4-benzyl-3-((2S)-2-ethoxy-3-{3-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one was subsequently saponified with 1N NaOH in THF to yield (S)-2-ethoxy-3-{3-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid as colorless solid. The enantiomeric excess was judged according to chiral HPLC (Chiralpak-AD) to be 99.3%.

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

Procedure: In analogy to the procedures described in examples 11 a] to 11 c], 7-[2-(5-methyl-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophene-4-carbaldehyde was reacted with (S)-4-benzyl-3-methoxyacetyl-oxazolidin-2-one and nBu2BOTf to yield (S)-4-benzyl-3-[(2S,3R)-3-hydroxy-2-methoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-4-yl}-propionyl]-oxazolidin-2-one (according to NMR, one of the four isomers is strongly predominating; the configuration was tentatively assigned as 2S, 3R according to Tetrahedron Asymmetry 1999, 1353). Reduction of (S)-4-benzyl-3-[(2S,3R)-3-hydroxy-2-methoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-4-yl}-propionyl]-oxazolidin-2-one with triethylsilane in trifluoroacetic acid then gave (S)-4-benzyl-3-(2(S)-methoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-4-yl}-propionyl)-oxazolidin-2-one. The (S)-4-benzyl-3-(2(S)-methoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-4-yl}-propionyl)-oxazolidin-2-one was subsequently saponified with 1N NaOH in THF to yield (S)-2-methoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-4-yl}-propionic acid as colorless solid.