(2R)-2-(cyclopentylmethyl)-4-[(2-methylpropan-2-yl)oxy]-4-oxobutanoic acid

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

Procedure: 4-(4-(S)-Benzyl-2-oxo-oxazolidin-3-yl)-3-(R)-cyclopentylmethyl-4-oxo-butyric acid tert-butyl ester (620 mg, 1.49 mmol, 1.0 eq.) was dissolved in THF (35 mL) and cooled in a 0° C. ice-water bath. Hydrogen peroxide (31 w/w %) (654 μL, 5.97 mmol, 4.0 eq.) and LiOH (72 mg, 2.98 mmol, 2.0 eq.) in water (7.5 mL) was added to the reaction mixture. The reaction stirred at 0° C. and judged to completion by LC/MS. Saturated sodium sulfite (18 mL) and sodium bicarbonate (18 mL) is added to the reaction. THF was evaporated by rotary evaporation and extracted the aqueous layer with CH2Cl2 (3×75 mL) to remove the chiral auxiliary. The aqueous layer was acidified at 0° C. with 6M HCl to pH˜1 and extracted with ethyl acetate (4×75 mL). The combined organic extracts were dried over MgSO4, filtered and evaporated to provide 281 mg (1.10 mmol, 73%) of 2-(R)-Cyclopentylmethyl-succinic acid 4-tert-butyl ester as clear oil and used directly in Step B. HPLC-MS calcd. for C14H24O4 (M+Na+) 279.3, found 279.3. THF was evaporated by rotary evaporation extracted the aqueous layer with CH2Cl2 (3×75 mL) to remove the chiral auxiliary was acidified at 0° C. with 6M HCl to pH˜1 extracted with ethyl acetate (4×75 mL) The combined organic extracts were dried over MgSO4 filtered evaporated

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

Procedure: 4-(4-(S)-Benzyl-2-oxo-oxazolidin-3-yl)-3-(R)-cyclopentylmethyl-4-oxo-butyric acid tert-butyl ester (620 mg, 1.49 mmol, 1.0 eq.) was dissolved in THF (35 mL) and cooled in a 0° C. ice-water bath. Hydrogen peroxide (31 w/w %) (654 μL, 5.97 mmol, 4.0 eq.) and LiOH (72 mg, 2.98 mmol, 2.0 eq.) in water (7.5 mL) was added to the reaction mixture. The reaction stirred at 0° C. and judged to completion by LC/MS. Saturated sodium sulfite (18 mL) and sodium bicarbonate (18 mL) is added to the reaction. THF was evaporated by rotary evaporation and extracted the aqueous layer with CH2Cl2 (3×75 mL) to remove the chiral auxiliary. The aqueous layer was acidified at 0° C. with 6M HCl to pH˜1 and extracted with ethyl acetate (4×75 mL). The combined organic extracts were dried over MgSO4, filtered and evaporated to provide 281 mg (1.10 mmol, 73%) of 2-(R)-Cyclopentylmethyl-succinic acid 4-tert-butyl ester as clear oil and used directly in Step B. HPLC-MS calcd. for C14H24O4 (M+Na+) 279.3, found 279.3. THF was evaporated by rotary evaporation extracted the aqueous layer with CH2Cl2 (3×75 mL) to remove the chiral auxiliary was acidified at 0° C. with 6M HCl to pH˜1 extracted with ethyl acetate (4×75 mL) The combined organic extracts were dried over MgSO4 filtered evaporated

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

Procedure: 4-(4-(S)-Benzyl-2-oxo-oxazolidin-3-yl)-3-(R)-cyclopentylmethyl-4-oxo-butyric acid tert-butyl ester (620 mg, 1.49 mmol, 1.0 eq.) was dissolved in THF (35 mL) and cooled in a 0° C. ice-water bath. Hydrogen peroxide (31 w/w %) (654 μL, 5.97 mmol, 4.0 eq.) and LiOH (72 mg, 2.98 mmol, 2.0 eq.) in water (7.5 mL) was added to the reaction mixture. The reaction stirred at 0° C. and judged to completion by LC/MS. Saturated sodium sulfite (18 mL) and sodium bicarbonate (18 mL) is added to the reaction. THF was evaporated by rotary evaporation and extracted the aqueous layer with CH2Cl2 (3×75 mL) to remove the chiral auxiliary. The aqueous layer was acidified at 0° C. with 6M HCl to pH ˜1 and extracted with ethyl acetate (4×75 mL). The combined organic extracts were dried over MgSO4, filtered and evaporated to provide 281 mg (1.10 mmol, 73%) of 2-(R)-Cyclopentylmethyl-succinic acid 4-tert-butyl ester as clear oil and used directly in Step B. HPLC-MS calcd. for C14H24O4 (M+Na+) 279.3. found 279.3. THF was evaporated by rotary evaporation extracted the aqueous layer with CH2Cl2 (3×75 mL) to remove the chiral auxiliary was acidified at 0° C. with 6M HCl to pH ˜1 extracted with ethyl acetate (4×75 mL) The combined organic extracts were dried over MgSO4 filtered evaporated

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

Procedure: 4-(4-(S)-Benzyl-2-oxo-oxazolidin-3-yl)-3-(R)-cyclopentylmethyl-4-oxo-butyric acid tert-butyl ester (620 mg, 1.49 mmol, 1.0 eq.) was dissolved in THF (35 mL) and cooled in a 0° C. ice-water bath. Hydrogen peroxide (31 w/w %) (654 μL, 5.97 mmol, 4.0 eq.) and LiOH (72 mg, 2.98 mmol, 2.0 eq.) in water (7.5 mL) was added to the reaction mixture. The reaction stirred at 0° C. and judged to completion by LC/MS. Saturated sodium sulfite (18 mL) and sodium bicarbonate (18 mL) is added to the reaction. THF was evaporated by rotary evaporation and extracted the aqueous layer with CH2Cl2 (3×75 mL) to remove the chiral auxiliary. The aqueous layer was acidified at 0° C. with 6M HCl to pH ˜1 and extracted with ethyl acetate (4×75 mL). The combined organic extracts were dried over MgSO4, filtered and evaporated to provide 281 mg (1.10 mmol, 73%) of 2-(R)-Cyclopentylmethyl-succinic acid 4-tert-butyl ester as clear oil and used directly in Step B. HPLC-MS calcd. for C14H24O4 (M+Na+) 279.3. found 279.3. THF was evaporated by rotary evaporation extracted the aqueous layer with CH2Cl2 (3×75 mL) to remove the chiral auxiliary was acidified at 0° C. with 6M HCl to pH ˜1 extracted with ethyl acetate (4×75 mL) The combined organic extracts were dried over MgSO4 filtered evaporated

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

Procedure: 4-(4-(S)-Benzyl-2-oxo-oxazolidin-3-yl)-3-(R)-cyclopentylmethyl-4-oxo-butyric acid tert-butyl ester (620 mg, 1.49 mmol, 1.0 eq.) was dissolved in THF (35 mL) and cooled in a 0° C. ice-water bath. Hydrogen peroxide (31 w/w %) (654 μL, 5.97 mmol, 4.0 eq.) and LiOH (72 mg, 2.98 mmol, 2.0 eq.) in water (7.5 mL) was added to the reaction mixture. The reaction stirred at 0° C. and judged to completion by LC/MS. Saturated sodium sulfite (18 mL) and sodium bicarbonate (18 mL) is added to the reaction. THF was evaporated by rotary evaporation and extracted the aqueous layer with CH2Cl2 (3×75 mL) to remove the chiral auxiliary. The aqueous layer was acidified at 0° C. with 6M HCl to pH˜1 and extracted with ethyl acetate (4×75 mL). The combined organic extracts were dried over MgSO4, filtered and evaporated to provide 281 mg (1.10 mmol, 73%) of 2-(R)— Cyclopentylmethyl-succinic acid 4-tert-butyl ester as clear oil and used directly in Step B. HPLC-MS calcd. for C14H24O4 (M+Na+) 279.3, found 279.3. THF was evaporated by rotary evaporation extracted the aqueous layer with CH2Cl2 (3×75 mL) to remove the chiral auxiliary was acidified at 0° C. with 6M HCl to pH˜1 extracted with ethyl acetate (4×75 mL) The combined organic extracts were dried over MgSO4 filtered evaporated

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

Procedure: To a 1000 ml round bottom flask under N2 was added (2R)-2-(cyclopentylmethyl)-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoic acid (Tetrahedron, 2001, 57(36), 7675-7683) (38.1 g, 149 mmol) in acetonitrile (650 mL) at 0° C., followed by N-methylmorpholine (82 mL, 744 mmol) and 4-[4,6-bis(methyloxy)-1,3,5-triazin-2-yl]-4-methylmorpholin-4-ium (53.7 g, 164 mmol). The solution was stirred at the same temperature for 2 hours and then (5S)-4,5-dihydro-1H-pyrazole-5-carboxylic acid, hydrochloride (22.4 g, 149 mmol) was added. The solution was allowed to warm up to room temperature and stirring continued overnight. LCMS showed that the reaction was complete. The acetonitrile was removed under reduced pressure, and the residue was taken up in DCM (500 mL) and neutralized by the addition of 2 N HCl. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by Combiflash automated silica gel chromatography (0-5% methanol containing 1% formic acid/DCM) to provide (5S)-1-{(2R)-2-(cyclopentylmethyl)-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoyl}-4,5-dihydro-1H-pyrazole-5-carboxylic acid (27.7 g, 79 mmol, 53% yield) as a clear oil. LCMS: [M+H]+: 353.4. stirring continued overnight The acetonitrile was removed under reduced pressure neutralized by the addition of 2 N HCl The organic phase was washed with brine dried over Na2SO4 filtered concentrated The residue was purified by Combiflash automated silica gel chromatography (0-5% methanol containing 1% formic acid/DCM)

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

Procedure: To a solution of (2R)-2-(cyclopentylmethyl)-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoic acid (Tetrahedron, 2001, 57(36), 7675-7683) (4.0 g, 15.60 mmol) in DCM was added pyridine (1.38 ml, 17.2 mmol) and a solution of 2,4,6-trifluoro-1,3,5-triazine (2.3 g, 17.2 mmol) in DCM (10 mL). The reaction was stirred at room temperature for 2 h. The solution was then washed with citric acid (20 mL×2) and brine (20 mL), then concentrated to provide the crude product, 1,1-dimethylethyl (3R)-3-(cyclopentylmethyl)-4-fluoro-4-oxobutanoate, as a yellow oil (3.8 g, 57% yield), which was used directly in the next step. MS: 257 ([M−H]+). The solution was then washed with citric acid (20 mL×2) and brine (20 mL) concentrated

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

Procedure: 4-(4-(S)-Benzyl-2-oxo-oxazolidin-3-yl)-3-(R)-cyclopentylmethyl-4-oxo-butyric acid tert-butyl ester (620 mg, 1.49 mmol, 1.0 eq.) was dissolved in THF (35 mL) and cooled in a 0° C. ice-water bath. Hydrogen peroxide (31 w/w %) (654 μL, 5.97 mmol, 4.0 eq.) and LiOH (72 mg, 2.98 mmol, 2.0 eq.) in water (7.5 mL) was added to the reaction mixture. The reaction stirred at 0° C. and judged to completion by LC/MS. Saturated sodium sulfite (18 mL) and sodium bicarbonate (18 mL) is added to the reaction. THF was evaporated by rotary evaporation and extracted the aqueous layer with CH2Cl2 (3×75 mL) to remove the chiral auxiliary. The aqueous layer was acidified at 0° C. with 6M HCl to pH˜1 and extracted with ethyl acetate (4×75 mL). The combined organic extracts were dried over MgSO4, filtered and evaporated to provide 281 mg (1.10 mmol, 73%) of 2-(R)-Cyclopentylmethyl-succinic acid 4-tert-butyl ester as clear oil and used directly in Step B. HPLC-MS calcd. for C14H24O4 (M+Na+) 279.3, found 279.3. THF was evaporated by rotary evaporation extracted the aqueous layer with CH2Cl2 (3×75 mL) to remove the chiral auxiliary was acidified at 0° C. with 6M HCl to pH˜1 extracted with ethyl acetate (4×75 mL) The combined organic extracts were dried over MgSO4 filtered evaporated