Synthesis of Benzyl-Protected Serine Derivative

N-benzyloxycarbonyl-L-serine benzyl ester (200 mg, 0.607 mmol) was placed in a flame dried round bottom flask and dissolved in anhydrous toluene to a concentration of 0.25 M (3 mL). Trichloroacetimidate 1 (239 mg, 0.728 mmol, 1.2 equiv) was added and the reaction warmed to reflux. After 24 hours the reaction still showed starting material by thin layer chromatography analysis, so more trichloroacetimidate 1 was added (239 mg, 0.728 mmol, 1.2 equiv). After another 24 hours at reflux the reaction was allowed to cool to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with 2M aq. NaOH (3×), dried (Na₂SO₄) and concentrated (this workup removes the trichloroacetamide byproduct). The residue was pre-adsorbed on silica gel and purified by silica gel column chromatography (15% ethyl acetate/hexanes) to provide 0.273 g (91%) of (S)-benzyl 3-(benzhydryloxy)-2-(((benzyloxy)carbonyl)amino) propanoate (23) as a clear oil. [α]_D^21.6 −12.5 (c 1.26, CHCl₃); TLC R_f = 0.18 (10% ethyl acetate/hexanes); IR (thin film from CH₂Cl₂) 3434, 3341, 3062, 3030, 2949, 2876, 1722, 1498, 1339, 1197, 1067 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.07–7.30 (m, 20H), 5.63 (d, J = 12.0 Hz, 1H), 5.19 (s, 1H), 5.12 (d, J = 4.0 Hz, 2H), 5.04 (s, 2H), 4.49 (dt, J = 2.8 Hz, 1H), 3.84 (dd, J = 9.4, 2.8 Hz, 1H), 3.60 (dd, J = 9.4, 3.1 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 170.3, 156.1, 141.6, 141.4, 136.4, 135.4, 128.7, 128.65, 128.6, 128.5, 128.4, 128.3, 128.2, 127.7, 127.0, 126.9, 84.2, 69.0, 67.4, 67.2, 54.8 (two signals in the aromatic region were not resolved.) Anal calcd for C₃₁H₂₉NO₅: C, 75.13; H, 5.90; N, 2.83. Found: C, 74.94; H, 5.97; N, 3.00. Chiral HPLC analysis: Chiralcel OD (heptane/2-PrOH = 90/10, 1.0 mL/min, 254 nm, 25 °C): t_{(S enantiomer)} = 16.7 min, t_{(R enantiomer)} = 23.9 min.