Dichloromethane → (3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester 8-methyl ester

Participants

Reaction Conditions

Reaction Steps

(S)-2-tert-Butoxycarbonylamino-3-{(S)-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-propionic acid methyl ester (4.9 g) was dissolved in 200 mL dry DCM and stirred on 0° C. bath. 100 mL 4N HCL in dioxane was added and the mixture stirred to rt over 3 h. The solvents were evaporated and the residue was evaporated from diethyl ether 4 times. 4 g of the residue was dissolved in 250 mL dry dioxane and 462 mg paraformaldehyde was added while stirring. Then 62.5 mL trifluoroacetic acid was added and the mixture was stirred 1.5 h. The solvents were then evaporated and the residue was dissolved in 250 mL EtOAc and 250 mL saturated aqueous NaHCO3, and 4.2 g di-t-butyl dicarbonate was added and stirred 18 h at rt. The layers were then separated and the organic layer was washed with brine, dried with Na2SO4, and evaporated. The residue was purified by silica gel flash chromatography (9:1 to 7:3 hexanes/EtOAc) to give 3.25 g after drying under vacuum. 1H NMR (400 MHz, acetone-d6): 7.72 (d, 1H), 7.61 (d, 1H), 7.51-7.42 (m, 3H), 7.12-7.07 (m, 2H), 0.680-6.70 (m, 2H), 5.20 (s, 2H), 5.13-5.07 (m, 1H), 5.02 and 4.76 (m, 1H), 4.66-4.52 (dd, 1H), 4.42 (d, 1H), 4.36-4.30 (m, 1H), 4.01 (m, 1H), 3.64 and 3.60 (s, 3H), 3.18-3.00 (m, 2H), 1.49 and 1.43 (s, 9H).

Provenance & Evidence