Sodium hydride → 6-tert-Butyl 1-ethyl (E)-(S)-5-[(tert-butoxycarbonyl)amino]-2-(3-fluoropropyl)hex-2-enedioate

Participants

Reaction Conditions

Reaction Steps

A solution of ethyl 2-(diethoxyphosphoryl)-5-fluoropentanoate (1.30 g, 4.12 mmol) in dry THF (15 mL) was added dropwise at 0° C. to a solution of sodium hydride (0.20 g, 60% on mineral oil, 4.94 mmol) in dry THF (35 mL). After stirring for 15 min tert-Butyl (S)-2-[(tert-butoxycarbonyl)amino]-4-oxobutanoate (1.13 g, 4.12 mmol) was added as a solution in dry THF (15 mL) dropwise to the reaction mixture. After stirring for 90 min at 0° C. the reaction was quenched by addition of saturated sodium bicarbonate solution (50 mL). After phase separation the aqueous layer was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried over sodium sulphate, concentrated under reduced pressure and the residue was purified by column chromatography (silica, hexanes/ethyl acetate gradient) to give 6-tert-Butyl 1-ethyl (E)-(S)-5-[(tert-butoxycarbonyl)amino]-2-(3-fluoropropyl)hex-2-ene-dioate and 6-tert-Butyl 1-ethyl (Z)—(S)-5-[(tert-butoxycarbonyl)amino]-2-(3-fluoropropyl)hex-2-enedioate as a mixture of diastereomers which were separated by HPLC (Chiralpak IC 5 μm 250×30 mm, hexane/2-propanol 90:10, 50 mL/min) to give 6-tert-Butyl 1-ethyl (E)-(S)-5-[(tert-butoxycarbonyl)amino]-2-(3-fluoropropyl)hex-2-enedioate (1e) (0.75 g, 1.86 mmol, 45%) and 6-tert-Butyl 1-ethyl (Z)—(S)-5-[(tert-butoxycarbonyl)amino]-2-(3-fluoropropyl)hex-2-enedioate (1d) (0.23 g, 0.56 mmol, 14%).

Provenance & Evidence