Reaction Steps
A precooled (0° C.) solution of t-butyl (R)-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-1-(4-((S)-2-methylbutoxy)phenyl)ethylcarbamate (250 mg, 0.55 mmol) and dichloromethane (10 mL) was treated dropwise with trifluoroacetic acid (2 mL). The resulting solution was maintained at room temperature for 16 h, then concentrated to afford a yellow oil that was dissolved in dichloromethane (5 mL) and added to a room temperature solution of 2-thiophen-2-yl-cyclopropane carbonylchloride (100 mg, 0.60 mmol), triethylamine (0.20 mL, 1.4 mmol) and dichloromethane (4 mL). The resulting reaction was maintained overnight, then transferred to a separatory funnel and partitioned between ethyl acetate (15 mL) and saturated aqueous sodium bicarbonate (15 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (15 mL). The combined organic layers were washed with water (15 mL) and brine (15 mL), then dried (MgSO4), filtered and concentrated to afford a residue that was purified by column chromatography on silica gel (10%→50% ethyl acetate in hexanes) to afford (S)-N-((R)-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-1-(4-((S)-2-methyl-butoxy)-phenyl)-ethyl)-2-phenyl-propionamide (220 mg, 81% yield) as a white powder: 1H NMR (400 MHz, CDCl3) δ 7.87 (dd, J=5.6, 3.0 Hz, 2H), 7.76 (dd, J=5.4, 3.2 Hz, 2H), 7.22-7.34 (m, 5H), 7.05 (d, J=8.6 Hz, 2H), 6.80 (d, J=8.8 Hz, 2H), 6.27 (d, J=8.1 Hz, 1H), 5.26 (td, J=8.3, 5.3 Hz, 1H), 3.86-3.90 (m, 2H), 3.79 (dd, J=9.1, 6.1 Hz, 1H), 3.70 (dd, J=8.8, 6.6 Hz, 1H), 3.50 (q, J=7.2 Hz, 1H), 1.80-1.90 (m, 1H), 1.52-1.59 (m, 1H), 1.39 (d, J=7.1 Hz, 3H), 1.23-1.32 (m, 1H), 1.01 (d, J=6.8 Hz, 3H), 0.96 (t, J=7.5 Hz, 3H); LRMS (ESI) m/e 485.0 [(M+H)+, calcd for C30H32N2O4 485.6].
