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0 °C

A solution of the free acid compound 4 (100 mg, 0.3055 mmol, 1.0 eq.) and L-proline benzyl ester hydrochloride (74 mg, 0.3055 mmol, 1.0 eq.) in dry CH2Cl2 (10 mL) was cooled at 0° C. 1-Hydroxybenzotriazole hydrate (HOBt) (42 mg, 0.3055 mmol, 1.0 eq.), N-ethyl-N′-(dimethylaminopropyl)-carbodiimide hydrochloride (EDC.HCl) (59 mg, 0.3055 mmol, 1.0 eq.) and iPr2NEt (0.10 mL, 0.6110 mmol, 2.0 eq.) were added and the resulting mixture stirred at 0° C. for 2 h. The cooling bath was removed and the reaction mixture then stirred for a further 48 h at room temperature. The reaction mixture was diluted with H2O (30 mL) and the extracted with EtOAc (3×30 mL). The combined organic extract were washed sequentially with saturated aqueous NaHCO3 (30 mL), brine (30 mL), and dried over anhydrous MgSO4. Evaporation of the solvent gave a crude residue, which was subjected to column chromatography on silica gel elution with 50% EtOAc-hexane afforded the desired compound (5S)-5-[(N-benzoyl)amino]-4-oxo-6-phenyl-hexanoyl-L-proline benzyl ester as a pale yellow viscous oil which foams (0.138 g, 88%); Rf 0.23 (50% EtOAc-hexane); IR (liquid film) ν 1726 (CO), 3200 (NH) cm−1; 1H NMR (300 MHz, CDCl3) δH 1.98 (2H, m, —CH2), 2.21 (2H, m, —CH2), 2.65 (2H, m, —CH2CO), 3.00 (1H, m, —CHαPh), 3.12 (1H, m, —CHβPh), 3.35 (2H, m, —CH2CO), 3.60 (2H, m, —CH2N), 4.52 (1H, m, —CHN), 5.03 (1H, m, —CH—), 5.14 (2H, dd, J=1.8 and 8.4 Hz, —OCH2Ph), 6.93 (1H, d, J=6.9 Hz, —NH—) and 7.15-7.77 (15H, m, Ar—H); 13C NMR (75 MHz, CDCl3) δC 22.8, 24.7, 28.3, 28.9, 29.2, 34.1, 34.6, 36.8, 46.5, 46.9, 58.9, 59.6, 66.7, 66.8, 126.8, 126.9, 127.0, 127.9, 128.3, 128.5, 128.7 (2C), 129.4, 131.6, 133.9, 135.7, 136.7, 166.9, 170.3, 171.9 and 207.4; HRMS m/z calcd for C31H32N2O5 (M+) 512.23436, found 512.23112.

1. customThe cooling bath was removed
2. stirringthe reaction mixture then stirred for a further 48 h at room temperature
3. additionThe reaction mixture was diluted with H2O (30 mL)
4. extractionthe extracted with EtOAc (3×30 mL)
5. extractionThe combined organic extract
6. washwere washed sequentially with saturated aqueous NaHCO3 (30 mL), brine (30 mL)
7. dry with materialdried over anhydrous MgSO4
8. customEvaporation of the solvent
9. customgave a crude residue, which
10. washwas subjected to column chromatography on silica gel elution with 50% EtOAc-hexane