Reaction Steps
{2-Benzyl-6-[(isoquinoline-1-carbonyl)-amino]-3,7-dioxo-[1,2]diazepan-1-yl}-acetic acid tert-butyl ester (7a) (115 mg, 0.23 mmol) was stirred in 20% of trifluoroacetic acid (TFA) in dichloromethane (2 mL) overnight. The solution was evaporated to afford {2-benzyl-6-[(isoquinoline-1-carbonyl)-amino]-3,7-dioxo-[1,2]diazepan-1-yl}-acetic acid (8a). 1H-NMR (500 MHz, CDCl3) δ 2.05-2.11 (m, 1H), 2,45-2.50 (m, 1H), 2.72-2.83 (m, 1H), 3.45-3.54 (m, 1H), 4.01-4.06 (d, 1H), 4.59-4.63 (d, 1H), 4.70-4.82 (m, 2H), 4.93-4.98 (d, 1H), 7.28-7.42 (m, 5H), 7.80-8.10 (m, 4H), 8.40-8.52 (m, 2H), 8.85 (d, 1H). The acid (8a) was dissolved in dichloromethane (2 mL) followed by addition of HOBT (77 mg, 0.57 mmol) and EDC (110 mg, 0.57 mmol) and stirred for 30 min. A solution of (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester (9, anti diastereomer) (166 mg, 0.57 mmol) in dichloromethane/DMF (3/1 mL), charged with 1,3-dimethylbarbituric acid (DMBA) (90 mg, 0.57 mmol) and Pd(PPh3)4 (66 mg, 0.057 mmol) for 30 min, was added and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (50 mL×3), dried over Na2SO4, filtered and evaporated to give a pale yellow solid, that was purified by flash chromatography using dichloromethane/methanol (99.5/0.5 to 98.5/1.5) to afford 97.5 mg (67% yield) of the title compound. 1H-NMR (500 MHz, CDCl3) δ 2.03-2.13 (m, 1H), 2.40-2.43 (d, 1H), 2.55-2.60 (m, 1H), 2.83-2.92 (m, 1H), 3.04-3.10 (q, 1H), 3.28-3.38 (m, 1H), 4.08-4.11 (d, 1H), 4.20-4.24 (d, 1H), 4.38-4.41 (m, 1H), 4.67-4.70 (d, 1H), 4.78-4.87 (m, 2H), 4.91-5.02 (m, 2H), 5.36 (s, 1H), 6.05 (d, 1H), 7.20-7.38 (m, 10H), 7.68-7.78 (m, 2H), 7.80-7.88 (m, 2H), 8.48 (d, 1H), 8.70 (d, 1H), 9.49 (d, 1H). Analytical HPLC: 12.53 min. LC-MS (ES+): m/e=636 (M+H+).
