methyl (2R)-3-hydroxy-2-(tritylamino)propanoate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of triphenylphosphine (3 eq) in dry THF under Argon was added diethylazodicarboxylate (3 eq) dropwise. The reaction mixture was stirred at room temperature for 15 minutes before adding a solution of 4-(trifluoromethyl)phenol (3 eq in dry THF) dropwise. The reaction mixture was stirred at room temperature for 1 hour before adding (R)-methyl 3-hydroxy-2-(tritylamino)propanoate (LXXXIX) in dry THF in one portion. The reaction mixture was stirred at room temperature ovenight. The mixture was concentrated to dryness, treated with hexane and filtered. The residue was concentrated to dryness and purified by silica flash chromatography (EtOAc/hexane=1:5). Pure (R)-methyl 3-(4-(trifluoromethyl)phenoxy)-2-(tritylamino)propanoate (XC) was obtained as an off-white solid (50% yield). The reaction mixture was stirred at room temperature for 1 hour The reaction mixture was stirred at room temperature ovenight The mixture was concentrated to dryness treated with hexane filtered The residue was concentrated to dryness purified by silica flash chromatography (EtOAc/hexane=1:5)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of D-Ser-OMe (LXXXVIII) in dry DCM was added TEA (1.2 eq). After the solution became clear, trityl chloride (1 eq in dry DCM) was added dropwise and stirred for 2 hours. The reaction mixture was washed with 2M HCl, brine and dried over anhydrous MgSO4. The solvent was removed under reduced pressure to give the crude product as a colorless oil. The oil crystallized from Et2O/hexane to produce pure (R)-methyl 3-hydroxy-2-(tritylamino)propanoate (LXXXIX) as white solid (85% yield). The reaction mixture was washed with 2M HCl, brine dried over anhydrous MgSO4 The solvent was removed under reduced pressure to give the crude product as a colorless oil The oil crystallized from Et2O/hexane

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S. Kato et al., J. Chem. Soc., Perkin Trans. 1997, 1, 3219-3225; J. Smrt et al., Experientia 1957, 15, 291). Crude (R)-methyl 3-hydroxy-2-(N-tritylamino)propanoate (45.20 g, 0.13 mol) was dissolved in CH2Cl2 (300 mL) and cooled to 0° C. under Ar. Methanesulfonyl chloride (10.64 mL, 0.14 mol) was added to the cooled solution, followed by the dropwise addition of Et3N (26.14 mL, 0.19 mol). The resulting solution was allowed to stir at 0° C. (30 min) and then successively washed with 10% aqueous citric acid (200 mL) and saturated aqueous brine (200 mL). After drying (Na2SO4) and evaporation of the solvent, the crude mesylate (53.30 g, 0.12 mol) was dissolved in DME (300 mL) and Et3N (33.73 mL, 0.24 mol) was added. The reaction mixture was stirred at 80° C. (48 h) and then evaporated in vacuo. The residue was dissolved in EtOAc (300 mL) and washed with 10% aqueous citric acid (200 mL) and saturated aqueous brine (200 mL). The organic layer was dried (Na2SO4) and evaporated in vacuo. The crude product was recrystallized (EtOH) to yield 30.81 g (74%) of desired product as a transparent crystal: mp 127-128° C. (Kato, S. et al., J. Chem. Soc., Perkin Trans. 1997, 1, 3219-3225; mp 129-131° C.); [α]20D +94.7° (c 1.5, CHCl3) (Smrt, J. et al., Experientia 1957, 15, 291; [α]20D +95 (c 1, CHCl3)); Rf=0.45 (1/5 EtOAc/hexanes); 1H NMR (CDCl3) δ 1.41 (dd, J=1.7, 6.4 Hz, NCHH′CH), 1.89 (dd, J=2.8, 6.4 Hz, CHH′CHN), 2.26 (dd, J=1.7, 2.8 Hz, NCHH′CH), 3.76 (s, OCH3), 7.20-7.31 (m, 9 PhH), 7.48-7.52 (m, 6 PhH); 13C NMR (CDCl3) δ 28.8 (NCH2CH), 31.8 (CH2CHN), 52.2 (OCH3), 74.5 (NCPh3), 127.1, 127.8, 129.4, 143.7 (3 C6H5), 172.0 (C(O)). successively washed with 10% aqueous citric acid (200 mL) and saturated aqueous brine (200 mL) After drying (Na2SO4) and evaporation of the solvent The reaction mixture was stirred at 80° C. (48 h) evaporated in vacuo The residue was dissolved in EtOAc (300 mL) washed with 10% aqueous citric acid (200 mL) and saturated aqueous brine (200 mL) The organic layer was dried (Na2SO4) evaporated in vacuo The crude product was recrystallized (EtOH)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S. Bhatia and J. Hajdu, Tetrahedron Lett. 1998, 29, 31-34). To a solution of D-serine methyl ester hydrochloride (20.00 g, 0.13 mol) and Et3N (35.82 mL, 0.26 mol) in CH2Cl2 (80 mL) at 0° C., was added in one portion a solution of TrCl (36.53 g, 0.13 mol) in CH2Cl2 (80 mL). The mixture was allowed to stir at 0° C. (24 h) under Ar and then successively washed with 10% aqueous citric acid (120 mL) and saturated aqueous brine (120 mL). The organic layer was dried (Na2SO4) and evaporated in vacuo to yield 45.20 g (97%) of crude desired product as a pale yellow crystalline solid. The product was used for next step without further purification: Rf=0.50 (1/1 EtOAc/hexanes); 1H NMR (CDCl3) δ 2.29 (br s, 1H), 2.98 (br s, 1H), 3.29 (s, OCH3), 3.51-3.60 (m, CHH′OH, CH), 3.64-3.74 (m, CHH′OH), 7.16-7.30 (m, 9 PhH), 7.47-7.50 (m, 6 PhH). successively washed with 10% aqueous citric acid (120 mL) and saturated aqueous brine (120 mL) The organic layer was dried (Na2SO4) evaporated in vacuo