General procedure for the synthesis of (R)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylates from methyl (2R,4R)-1-Boc-4-hydroxypyrrolidine-2-carboxylate:
Step 1: Oxidation reaction
Pyridinium dichromate (9.97 g, 26.5 mmol) was dissolved in dichloromethane (60 mL) at room temperature and slowly added to a dichloromethane solution of methyl (2R,4R)-1-Boc-4-hydroxypyrrolidine-2-carboxylate (5.00 g, 20.39 mmol). The reaction mixture was stirred at room temperature overnight. After completion of the reaction, diatomaceous earth (5 g) was added and stirring was continued for 40 min, followed by filtration. The filter cake was washed with dichloromethane (50 mL x 3). The filtrates were combined, concentrated to dryness under reduced pressure, added toluene (40 mL) and concentrated again to give about 6.5 g of brown slurry-like crude product.
Purification step
The crude product was purified by fast silica gel column chromatography (120 g silica gel column, eluent EtOAc/hexane, gradient 0 to 100%, flow rate 85 mL/min) to afford 4.18 g (84% yield) of (R)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate as a white solid.
Product characterization
LCMS (condition A): m/z 144 (M-Boc)-ve.
1H NMR (400 MHz, CDCl3) δ ppm: 4.44-4.89 (1H, m), 3.84-3.96 (2H, m), 3.77 (3H, s), 2.81-3.10 (1H, m), 2.59 (1H, dd, J = 18.93, 1.76 Hz), 1.52 (9H, s).
