4-Methylmorpholine → (2S,4R)-tert-butyl 2-((1R,2S)-1-(ethoxycarbonyl)-2-vinylcyclopropylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylate

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Reaction Conditions

Reaction Steps

To a solution of 4.87 g (21.0 mmol) of Boc-(2S,4R)-hydroxyproline in 25 mL of THF 2.03 mL (20.0 mmol) of NMM was added. A suspension was formed. The mixture was cooled to −23° C. and 2.85 g (20.0 mmol) of isobutylchloroformiate was added. After stirring for 10 min additional 4.25 g (42.0 mmol) of NMM was added. To this mixture the solution of (1R,2S)-1-amino-2-vinyl-cyclopropanecarboxylic acid ethyl ester prepared in example 1 was added at a temperature of −15° C. within 5 min. The reaction mixture was stirred for 2.5 h at 0° C. Salts were filtered off and the filtrate was treated with 20 mL of aqueous HCl (0.5 N). The solvents were removed at 50° C. under reduced pressure using a rotary evaporator and the residue was extracted twice with 50 mL of EtOAc. The extract was washed with 40 mL of water and 40 mL of aqueous Na2CO3 solution (10 wt %), and dried over sodium sulfate. Finally the solvent was removed completely to give 8.19 g of (2S,4R)-2-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester as a yellow oil. The product was used in the next step without further purification.

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