GENERAL PROCEDURE: (R)-2-(2-(tert-butoxy)-2-oxoethyl)-4-methylpentanoic acid was prepared according to Scheme 2 (steps a-d).
Step a: To a solution of 3-cyclopentylpropionic acid (46.6 g, 0.33 mol) in freshly distilled anhydrous THF (0.9 M) was added triethylamine (52 mL, 0.38 mol), the mixture was cooled to -78 °C and pivaloyl chloride (41 mL, 0.33 mol) was added dropwise. After stirring at -78 °C for 15 minutes, the mixture was warmed to room temperature and stirring was continued for 1 hour (a white suspension was formed).
Step b: To a solution of (S)-4-benzyloxazolidin-2-one (59.2 mg, 0.33 mol) in freshly distilled THF was added nBuLi (2.5 M solution in THF, 134 mL, 0.33 mol) and the mixture was stirred for 20 min at -78 °C. Subsequently, the mixture was added to the above pre-cooled (-78 °C) pivalic anhydride. The reaction mixture was stirred at -78 °C for 30 min and then the cooling bath was removed to bring the reaction to room temperature. Saturated aqueous NH4Cl solution (500 mL) was added and the aqueous phase was extracted with EtOAc (2 x 200 mL). The organic extracts were combined, dried with MgSO4, filtered and concentrated in vacuum. Rapid chromatographic purification of the crude product using a petroleum ether solution of 20% EtOAc afforded 91 g (91%) of (S)-4-benzyl-3-(3-cyclopentylpropionyl)oxazolidin-2-one (34) as a white solid.
Step c: NaHMDS (1 M, THF, 410 mL, 0.41 mol) was added dropwise to a stirred solution of 34 (95 g, 0.315 mol) in THF (0.08 M) at -78 °C over 1 h, followed by tert-butyl bromoacetate (70 mL, 0.41 mol) dropwise over 30 min. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature and stirred overnight. Subsequently, the mixture was cooled with an ice bath, saturated aqueous NH4Cl solution (300 mL) and water (100 mL) were added slowly and the aqueous phase was extracted with EtOAc (200 mL). The organic extracts were combined, dried with Na2SO4, filtered and evaporated to dryness. The crude product was purified by fast chromatography using a petroleum ether gradient of 5-30% EtOAc to afford 73 g (56%) of tert-butyl (R)-4-((S)-4-benzyl-2-oxoxoxazolidin-3-yl)-3-(cyclopentylmethyl)-4-oxobutanoate (38) as a white solid.
Step d: To a stirred solution of 38 (73 g, 0.18 mol) in 750 mL THF/water (4:1, v/v) was added H2O2 (35% aqueous solution, 68 mL, 0.7 mol) dropwise over 15 min at 0 °C. After continued stirring for 10 min, 1 M aq LiOH (300 mL, 0.35 mol) was added dropwise over 15 min, followed by warming the mixture to room temperature and stirring for 16 h until the completion of the reaction was confirmed by LCMS. The reaction mixture was cooled with an ice bath and an aqueous (1 L) solution of sodium bisulfite (225 g, 1.8 mol) was added dropwise over 1 h (note: this process is slightly exothermic). Most of the THF was removed in vacuo, and the resulting aqueous layer (pH ~12) was washed with Et2O (3 × 500 mL), cooled (ice bath) and acidified to pH 1 with 6 M HCl. The extract was extracted with EtOAc (5 × 500 mL), the extracts were combined, dried over MgSO4, filtered and concentrated to dryness in vacuo to give (R)-2-(2-(tert-butoxy)-2-oxoethyl)-4 -methylpentanoic acid (42) (30 g, 65%) as a light yellow oil.
