Tetrahydrofuran → (S)-3-((S)-cyclopropylhydroxymethyl)pyrrolidine-1-carboxylic acid t-butyl ester

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Reaction Conditions

Reaction Steps

(S)-3-Formyl-pyrrolidine-1-carboxylic acid t-butyl ester (1.0 g, 5 mmol) and THF (10 mL, 100 mmol) were combined under nitrogen, and the resulting solution was cooled to −78° C. 0.5M Cyclopropylmagnesium bromide in THF (15 mL, 7.5 mmol) was then added dropwise over 10 minutes. The mixture was allowed to warm to room temperature slowly overnight. Then aqueous saturated NH4Cl (30 mL) was added dropwise to quench the reaction. The resulting mixture was extracted with EtOAc (2×30 mL), and the combined organic layers were washed with saturated aqueous NaHCO3 (1×30 mL) and saturated aqueous NaCl (1×30 mL), then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC (15-55% MeCN:H2O+0.05% TFA over 80 minutes) on a 2″ column to yield (S)-3-((R)-cyclopropylhydroxymethyl)pyrrolidine-1-carboxylic acid t-butyl ester (520 mg, 2nd eluting peak) and (S)-3-((S)-cyclopropylhydroxymethyl)pyrrolidine-1-carboxylic acid t-butyl ester (418 mg, 1st eluting peak). The lyophilized solids were dissolved in EtOAc and washed with saturated aqueous NH4CO3, the organics were separated, dried over Na2SO4 and the solvent was removed under reduced pressure.

Provenance & Evidence