Z-ASP-OBZL

Colourless Solid

Preparation of (2S)-2-Benzyloxycarbonylamino-4-oxo-hexanedioic acid 1-benzyl ester 6-ethyl ester. According to the method described by Brooks, to a solution of the Cbz-(L)-Asp-OBn (7.41 g, 20.74 mmol) in THF (4 mL/mmol) carbonyldiimidazole (3.7 g, 22.82 mmol, 1.1 equiv) was added at room temperature. The resulting reaction mixture was stirred two hours at room temperature, then cooled at 0C before addition of magnesium bis(monoethylmanolate) (3.21 g, 11.20 mmol, 0.54 equiv). The reaction mixture was stirred overnight at room temperature as slow CO2 release was observed. It was taken up in ether (15-20 mL/mmol of amino acid) and acidified with concentrated HCl (1 N or 6N) at 0C; the ethereal extract was washed with 10% NaHCO3, 4:1 H2O/KHSO4(1M), H2O and brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (1: 1 EtOAc/cyclohexan), leading to example (1) (6.83 g, 16.0 mmol, 77%) as a white solid. 1H-NMR (400 MHz, CDCl3): 1.26 (t, 3H, J = 7.2), 3.15 (dd, 1 H, J = 18.6, 4.2), 3.32 (dd, 1 H, J = 18.6, 4.2), 3.42 (s, 2H), 4.17 (q, 2H, J = 7.2), 4.52-4.71 (m, 1 H), 5.12 (s, 2H), 5.17 (s, 2H), 5.78 (d, 1 H, J = 8.4), 7.33 (m, 10H). 13C-NMR (CDCl3): 13.7, 44.2, 48.7, 49.5, 61.2, 66.7 and 67.2, 127.7, 127.8, 127.8, 128.0, 128.1 and 128.2, 134.8 and 135.7, 155.6, 166.1, 170.2 and 200.4.A solution of Cbz-(L)-Asp-OBn and carbonyldiimidazole (1.1 eq) in THF was stirred for two hours at ambient temperature, cooled to 0C and 0.54 eq. of monoethyl malonic acid magnesium salt was added. The mixture was stirred overnight at ambient temperature. The mixture was diluted with ether (15 ml.) and acidified with cone. HCI at 0C and the two phases separated. The organic phase was washed with 10% NaHC03, 4:1 H20:KHSO4(1 M), H20 and brine, dried over MgS04and the solvent removed. A final flash purification (1 : 1 EtOAc:hexane) resulted in 1 .67 g (70 %) of compound 16 as a white solid. The analytical data matched the literature (M. P. Brun, L. Bischoff, C. Garbay, Angew Chem Int Ed Engl 2004, 43, 3432-3436).