Chloroacetic anhydride is a nasty irritant: use gloves, do not spill, do not inhale vapors. The anhydride should look like a nice white crystalline solid. If soggy or dark, purify it before use by vacuum distillation (on Kugelrohr).
LAH 12.5g was added in 1 gram-sized portions into a vigorously-stirred solution of Cbz-D-Serine(OtBu)-OH 25.05g (84.8mmol) in anh. THF 0.5L in a 2L flask with cooling on ice bath. After complete LAH addition, the mix was refluxed for 6 hours. The reaction mixture was cooled to 0C, quenched very slowly by carefull addition of water 12.5mL (dropwise!), then 15% aq. NaOH (37.5mL) and then additional water (12.5mL). The mixture was stirred for 12 hours (overnight), filtered, the salts were thoroughly washed with THF and discarded. The filtrates were evaporated. The residue was dissolved in dichloromethane 100mL, cooled to 0C and a solution of chloroacetic anhydride 17.10g (100mmol) in dichloromethane (40mL) was added dropwise over 90min with cooling at 0C (addition funnel was used). The mixture was stirred at 0C for additional 30 min, the cooling bath was removed, the acylation was quenched by addition of sat NaHCO3 (300mL), stirred in an open flask at RT for 30 min. The org. phase was separated, washed with sat. NaHCO3 300ML, the aqueous phases were re-extracted with dichloromethane (2x150mL). The combined org. extracts were dried (MgSO4) and evaporated, the residue was dried on highvac. (0.5Torr, 60C, 1h). The residue was dissolved in anhydrous ethanol 150mL (non-denaturated), sodium methoxide 5.40g (100mmol) was added (in 3 portions) with cooling on ambient water bath. The mixture was stirred at RT for 10 min, then at 60C for 30 min. The obtained heterogennos mixture was evaporated, the residue was portioned between sat. ammonium chloride 150mL and chloroform 100mL. The aqueous phase was re-extracted with additional chloroform (3x100mL). The combined extracts were dried (MgSO4) and evaporated, the residue was distilled on Kugelrohr at 0.5 Torr, 90-130C air bath temp.
The obtained crude tBu-protected morpholinone (semi-solid distillate from Kugelrohr) was combined with TFA 100mL. The mixture was stirred for 2 hours, evaporated on highvac and re-evaporated with toluene. The obtained trifluoroacetate ester was dissolved in methanol 60mL, made basic by addition of concentrated aq. NH3 (12mL), stirred for 1 hour then evaporated and dried on highvac. The residue was stirred twice with cyclohexane (2x100mL), the upper phase decanted off, the bottom phase was heated with toluene 100mL to reflux, cyclohexane 100mL was added, stirred for 1 hour at RT, the upper phase was decanted off. (This washing excersize was done to remove benzyl alcohol that carried over from the LAH reduction). The residue was dissolved in a 10:1 mixture of chloroform-methanol (10:1, 60mL), stirred for 30 min, the precipitated salts were removed by filtration (and washed with the 10:1 mixture), the filtrates were evaporated. The residue was purified on a column of silica (200g) in 10:1 chloroform-methanol mixture. The purified product was dried on highvac. Y=11.61g (94% overall) of a colorless honey.
1H(CDCl3, 400MHz): 4.143(m, 3H), 3.834(m, 3H), 3.294(m, 1H), 3.046(s, 3H), 2.719(br s, 1H); 13C(CDCl3, 100MHz): 167.73, 67.77, 64.73, 60.27, 58.93, 33,36(br s)
Using identical procedure, Cbz-L-Ser(OtBu)OH provided the S-enantiomer in 94%Y overall (11.63g)