The general procedure for the synthesis of Fmoc-L-allylglycine from (S)-(-)-2-amino-4-pentenoic acid and 9-fluorenylmethyl-N-succinimidyl carbonate is as follows:
7.14.1 Preparation of 2-N-fluorenylmethoxycarbonylaminopent-4-enoic acid (Fmoc-Hag-OH)
Allylglycine derivatives were prepared according to Paquet's method. Fmoc-OSu (14.60 g, 43.3 mmol) was added to a solution of L-allylglycine (5.00 g, 43.5 mmol) and NaHCO3 (18.20 g, 0.22 mol) in acetone:water (200 mL) mixture under stirring conditions. The resulting white suspension was stirred at room temperature for 20 h. Complete consumption of the raw material was confirmed by thin layer chromatography (TLC, silica gel plate, light petroleum ether:ethyl acetate = 1:1) analysis. The reaction mixture was acidified to pH 2 with concentrated hydrochloric acid and acetone was removed under reduced pressure. The resulting suspension was extracted with dichloromethane (DCM, 3×75 mL), and the organic phases were combined, washed sequentially with dilute hydrochloric acid (1M, 2×50 mL), water (2×50 mL), dried (MgSO4), and concentrated under reduced pressure to afford the target product Fmoc-amino acid 96 as a colorless solid (14.01 g, 96% yield) with a melting point of 137-138 °C (literature value (134-136°C).
IR spectrum (KBr, cm-1): 3484 (s), 3198 (bs), 3085 (m), 2967 (m), 2923 (m), 1723 (s), 1644 (m), 1525 (s), 1478 (w), 1449 (s), 1396 (m), 1340 (m), 1233 (s), 1189 (s). 1099(m), 1048(s), 998(w), 966(w), 943(m), 924(w), 850(m), 781(m), 761(s), 740(m), 648(w), 623(m), 582(m), 560(w), 540(m), 424(w).
1H NMR (400MHz, CDCl3): δ 2.52-2.70 (m, 2H, H3), 4.23 (t, J=6.9Hz, 1H, H9'), 4.42 (d, J=6.9Hz, 2H, CH2O), 4.52 (m, 1H, H2), 5.13-5.23 (m, 2H, H5), 5.31 (bd, J= 7.8 Hz, 1H, NH), 5.75 (m, 1H, H4), 6.63 (bs, 1H, OH), 7.31 (td, J=7.4,0.8 Hz, 2H, H2',7'), 7.38 (t, J=7.4 Hz, 2H, H3',6'), 7.52-7.63 (m, 2H, H1',8'), 7.76 (d, J = 7.5 Hz, 2H, H4',5'), no exchangeable protons (OH) were observed.
13C NMR (100 MHz, CDCl3): δ 36.7 (C3), 47.5 (C9'), 53.4 (C2), 68.1 (CH2O), 122.0 (C5), 120.1 (C2',7'), 125.4 (C3',6'), 127.9 (C1',8'), 128.0 (C4',5') 131.1 (C4), 141.7 (C8'a,9'a), 144.0 (C4'a,4'b), 156.3 (OCONH), 176.4 (C1).
Mass spectrum (ESI+, MeOH): m/z 338.4 ([M+H]+, calculated value 338.1, C20H20NO4), 360.3 ([M+Na]+, calculated value 360.1, C20H19NNaO4). The spectral data are in agreement with those reported in the literature.
