Reaction Steps
N-tert-butoxycarbonyl O-propynyl-L-serine 13 (6.26 g, 25.7 mmol) was dissolved in DMF (50 mL). Aminoisobutyric acid methyl ester hydrochloride 2 (3.95 g, 25.7 mmol) was dissolved in DMF (50 mL) and N,N-diisopropylethylamine (3.32 g, 25.7 mmol) added. The resulting solution was added to the solution of 13 in one portion and the mixture cooled to 0° C. (ice bath). HOBt hydrate (3.94 g, 25.7 mmol) and then EDC hydrochloride (5.43 g, 28.3 mmol) were added in portions together with additional DMF (50 mL). The reaction mixture was stirred for 1 h at 0° C., after which the ice bath was removed and stirring continued for 42 h at room temperature. The solvent was evaporated and the residue taken up in EtOAc (300 mL). The solution was washed with 2 M HCl (3×100 mL), 7.5% (w/w) K2CO3 solution (3×100 mL) and brine (100 mL). The solution was dried with anhydrous MgSO4 and the solvent evaporated affording a yellow/orange, viscous oil which was deemed to be of satisfactory purity to be used in subsequent steps without further purification (7.94 g, 90%); 1H NMR (300 MHz, DMSO-d6) δ 8.23 (s, 1H, NH(Aib)), 6.69 (d, J=8.5 Hz, 1H, NH(propSer), rotamer 1), 6.32 (d, 1H, NH(propSer), rotamer 2), 4.21-4.08 (m, 1H, CαH), 4.13 (d, J=2.1 Hz, 2H, CH2CCH), 3.57 (dd, J=9.9, 4.8 Hz, 1H, CHH), 3.54 (s, 3H, OCH3), 3.47 (dd, J=9.6, 7.4 Hz, 1H, CHH) 3.42 (t, J=2.3 Hz, 1H, CCH), 1.38 (s, 9H, (CH3)3), 1.35 (s, 3H, CH3), 1.33 (s, 3H, CH3); 13C NMR (75 MHz, d6-DMSO) δ 174.0, 169.0, 154.9, 79.9, 78.1, 77.1, 69.3, 57.5, 54.9, 53.7, 51.7, 28.0, 24.6; HRMS (m/z): [M+Na]+ calcd. for C16H26N2O6Na, 365.1688. found, 365.1695; Anal. Calcd. for C16H26N2O6: C, 56.13; H, 7.65; N, 8.18. Found: C, 56.1; H, 7.7; N, 8.0.
