Toluene → Ethyl (9aS)-4-{2-[(benzylamino)carbonyl]cyclopropyl}-5-oxo-2-{2-[4-(trifluoromethyl)phenyl]ethyl}-7,8,9,9a-tetrahydro-5H-pyrido[2,3-a]pyrrolizine-3-carboxylate

Participants

Reaction Conditions

Reaction Steps

ArgoGel-OH (0.50 g, 0.44 meq/g, 0.22 mmol) was suspended in toluene (5 mL) tert-butyl (2S)-2-[(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)carbonyl]-1-pyrrolidinecarboxylate (0.85 g, 0.25 mmol) was added. The sealed reaction tube was heated at 80° C. for 23 h. The reaction mixture was allowed to cool to room temperature and filtered. The resin was washed (DMF then DCM then ether; 8× each) and suspended in 5 mL anhydrous DMF and 2-formylcyclopropanecarboxylic acid (0.25 g, 2.2 mmol) was added followed by piperidine (0.04 mL), and trimethyl orthoformate (0.15 mL). After 14 h at 65° C., the resin was filtered and washed as above and resuspended in 5 mL fresh DMF. Ethyl (2Z)-3-amino-5-[4-(trifluoromethyl)phenyl]-2-pentenoate (0.63 g, 2.2 mmol) was added followed by trimethyl orthoformate (0.15 mL) and the sealed reaction mixture was heated at 80° C. for 16 h. The resin was filtered and washed as before. The resin was suspended in DCM (5 mL) and DDQ (0.13 g, 0.55 mmol) was added. The brown suspension was shaken at room temperature for 30 min then filtered and washed as before. The resin was dried overnight at 30° C. under high vacuum. The resin (0.15 g, 0.05 mmol) was suspended in 2 mL DMF and 0.5 mL pyridine. Pentafluorophenyl trifluoroacetate (0.13 g, 0.5 mmol, 0.08 mL) was added and the sealed reaction tube was shaken at room temperature for 45 min, filtered and washed as above and dried under high vacuum overnight. The resin was suspended in DCM (2 mL) and DMAP (25 mg) and benzylamine (0.05 mL) were added and the reaction mixture was shaken at room temperature for 4 h. The resin was filtered and washed as before. The resin was suspended in 1 mL TFA:DCM:phenol:thioanisole (70:20:5:5) and shaken for 0.5 h, filtered and washed. The resin was shaken in 2 mL 5% TEA in DCM for 24 h. The resin was filtered into a collection flask and rinsed with additional DCM (3×). The filtrate was concentrated and the product was purified by preparative thin-layer chromatography (SiO2, hexanes:EtOAc 1:5) then triturated in a mixture of DCM and hexanes to provide the title compound as white solid (4 mg, 0.07 mmol, 80%): 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J=8.4 Hz, 2H), 7.4–7.3 (m, 4H), 7.05 (t, J=5.6 Hz, 1H), 4.63–4.48 (m, 2H), 4.46–4.31 (m, 3H), 3.79–3.72 (m, 1H), 3.44–3.38 (m, 1H), 3.16–3.06 (m, 4H), 2.50–2.25 (m, 4H), 2.180 (m, 1H), 1.73 (m, 1H), 1.40–1.21 (m, 3H), 1.35 (t, J=7.2 Hz, 3H) ppm. ESMS m/z 592 (M+H)+; (neg. ion) 590 (MH)+.

Provenance & Evidence