Dabco → N1-butyl-N3-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R)-4-hydroxy-4-phenylpyrrolidin-2-yl)propan-2-yl)-N1-methylisophthalamide

Participants

Reaction Conditions

Reaction Steps

Step 6 (A): (2R,4R)-tert-butyl 2-((1S,2S)-2-(benzyloxycarbonyl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)-4-hydroxypyrrolidine-1-carboxylate. To a solution of (2R,4R)-tert-butyl 4-(allyloxy)-2-((1S,2S)-2-(benzyloxycarbonyl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)pyrrolidine-1-carboxylate (Preparation A, 730 mg, 1.11 mmol) in H2O/EtOH (0.8/7 mL) were added RhCl(PPh3)3 (77 mg, 0.083 mmol) and DABCO (25 mg, 0.22 mmol). The mixture was stirred at 140° C. for 3 h and then cooled to rt. MeOH (20 mL) and 1N NaOH solution (5 mL) were added followed by 0.1% KMnO4 solution (5 mL) dropwise. The reaction mixture was stirred at rt for 1.5 h and quenched with H2O. The mixture was extracted with ethyl acetate (300 mL) twice and solvent was removed. Flash chromatography (silica gel, 0% to 10% to 20% to 35% EtOAc/Hexane step gradient) gave the title compound (530 mg, 77% yield): 1H NMR (CDCl3, 500 MHz) δ 0.10-0.13 (6H, m), 0.93 (9H, s), 1.22-1.27 (2H, m), 1.46 (9H, s), 2.13 (2H, s), 3.23-3.25 (2H, m), 3.54-3.89 (2H, m), 4.12 (1H, m), 4.22 (1H, s), 4.32 (1H, m), 4.86-5.03 (3H, m), 6.60-6.70 (3H, m), 7.17 (2H, s), 7.27-7.28 (3H, m). MS (ESI) (M+H)+ 621.25.

Provenance & Evidence