(2S)-1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylic acid → (2S)-1-((tert-butoxy)carbonyl)-4-methylidenepyrrolidine-2-carboxylic acid

Participants

Reaction Conditions

Reaction Steps

To a mixture of methyltriphenylphosphonium bromide (236.4 g, 2.7 eq) in THF (1 L) was rapidly added potassium tert-butoxide (75.6 g, 2.75 eq) while maintaining the temperature around 0° C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 2 hours, and re-cooled to 0° C. (S)-1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylic acid (56.2 g, 0.245 mol) was added portionwise to the reaction mixture while maintaining the temperature below 5° C. Then, the reaction was allowed to warm to room temperature and stirred at room temperature overnight before being re-cooled to 0° C. and quenched by addition of saturated NaHCO3 solution (500 mL) and water (200 mL). The mixture was evaporated. The aqueous layer was extracted with tert-butyl methyl ether (2×400 mL). The aqueous layer was filtered through a pad of celite and the filtrate was acidified with 6N HCl (200 mL) and extracted with ethyl acetate (2×1 L). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated to dryness. The residue was dissolved in ethyl acetate (0.7 L), extracted with 0.5 N NaOH (0.7 and 0.3 L). The aqueous layer was acidified with 6N HCl (100 mL), extracted with ethyl acetate (1 L and 0.8 L). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated to dryness. The residue was dissolved in 50% ethyl acetate in cyclohexane (150 mL), slowly evaporated to give a yellowish solid. It was filtered and dried to give the title compound (26 g). The filtrate was evaporated to give a yellowish solid, filtered and dried to provide the title compound (10 g). Total 36 g (65%) as a white solid. Also, the residue contained 18 g of the product as 80% purity. 1H NMR (500 MHz, CDCl3): 5.04-5.02 (m, 2H), 4.53 (dd, J=8.4, 3.2 Hz, 0.5H), 4.42 (d, J=9.3 Hz, 0.5H), 4.09-3.98 (m, 2H), 3.05-2.69 (m, 2H), 1.49 and 1.43 (2 s, 9H).

Provenance & Evidence