Methyl iodide → (2R,3S,5R)-5-[(1S,2S)-1-benzyloxy-2-dibenzylamino-3-(4-methyl-3,5-difluorophenyl)-propyl]-2-(2,2-dimethylpropoxy)-3-methylmorpholine-4-carboxylic acid tert-butyl ester

Participants

Reaction Steps

Add n-butyllithium (252 μL, 0.404 mmol, 1.6 M in hexanes) dropwise over 5 minutes to a solution of (2R,3S,5R)-5-[(1S,2S)-1-benzyloxy-2-dibenzylamino-3-(3,5-difluorophenyl)-propyl]-2-(2,2-dimethylpropoxy)-3-methylmorpholine-4-carboxylic acid tert-butyl ester (0.30 g, 0.404 mmol) in tetrahydrofuran (0.6 mL) at −78° C. Add potassium tert-butoxide (0.404 mL, 1 M in tetrahydrofuran) dropwise over 10 minutes and stir the reaction mixture for an additional 10 minutes. Add iodomethane (25.1 μL, 0.404 mmol) followed by a solution of hexamethylphosphorus triamide (53.7 μL, 0.294 mmol) in tetrahydrofuran (40.4 μL). Stir reaction mixture at −78° C. for 1 hour. Remove cooling bath and stir for 20 minutes. Add water (20 mL) and extract with ethyl acetate (2×50 mL). Wash combined organic layers with water (3×20 mL), dry over magnesium sulfate, and concentrate under reduced pressure. Subject residue to silica gel chromatography, eluting with hexanes containing 0-10% diethyl ether, to provide the desired compound 0.169 g (55.3%) as a white foam.

Provenance & Evidence