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To a stirred solution of <strong>[61636-32-6]4-benzylmorpholin-3-one</strong> (5.02 g, 26 mmol) in anhydrous THF (25 ml) under nitrogen [AT-78C] was added a 2 M. solution [OF LDA] in [HEPTANE/THF/ETHYLBENZENE] (1.5 eq. , 39 mmol, 19.5 ml) over approximately 20 minutes, whilst maintaining the reaction temperature [BELOW-75C.] The resulting brown solution was stirred for a further 30 minutes [AT-78C,] before being slowly added over approximately 30 minutes to a solution of benzaldehyde (1.2 eq. , 3.34 g, 31 mmol) in anhydrous THF (15 ml) under nitrogen [AT-78C,] whilst again maintaining the reaction temperature [BELOW-75C.] The resulting yellow solution was stirred at-78C for 1 hour, before being allowed to warm to room temperature slowly over 1 hour. The reaction mixture was cautiously quenched by addition of saturated ammonium chloride solution (50 ml) and the THF was evaporated [IN VACUO] from the mixture. The resulting cloudy aqueous solution was extracted with DCM (3 x 50 ml), and the organic extracts were combined, washed with brine (50 ml), dried over [NA2S04] and the DCM evaporated in vacuo to give a thick brown oil (9.2 g), which partially crystallised on standing. The mixture of diastereoisomeric alcohols was purified and separated by flash column chromatography using gradient elution (from 10% EtOAc, 90% DCM to 20% EtOAc, 80% DCM), which gave (2R)-4-benzyl-2- [ (S)-hydroxy (phenyl) methyl] morpholin-3-one and (2S)-4-benzyl-2- [ (R)-hydroxy (phenyl) methyl] morpholin-3-one as light red crystals (2.461 g, 31% yield); [MW] 297.36 ; [C18H19NO3] ; [RF 0.] 40 (50% EtOAc, 50% hexane); 1H NMR (CDC13): 7.41-7. 36 (2H, m), 7.31-7. 16 (6H, m), 6.91-6. 86 (2H, m), 5.14 [(1H,] d, J 3.5 Hz), 4.71 [(1H,] d, 14.5 Hz), 4.48 [(1H,] d, J 3.5 [HZ),] 4.25 [(1H,] d, 14.5 Hz), 4.20 [(1H,] br. s), 3.89 [(1H,] ddd, 11. [7 HZ,] 2. [5 HZ,] 2. [0 HZ),] 3.67 [(1H,] dt, 11. [2 HZ,] 3. [4 HZ),] 3.16 [(1H,] dt, 12.0 Hz, 4.0 Hz), 2.86 [(1H,] br. d, 12.0 Hz); LCMS: m/z 298 [M+H] + [&COMMAT; ] Rt 1.24 min (single major peak). This reaction was performed on scales from 200 mg to 5 g (yield range 20 to 40%). [(2R)-4-BENZYL-2-[(R)-HYDROXY] (phenyl) methyl] morpholin-3-one and [(2S)-4-BENZYL-2-[(S)-HYDROXY] (phenyl) methyl] morpholin-3-one diastereoisomer was isolated as a brown solid (1.42 g) contaminated with N-benzylmorpholin-3-one. Trituration with EtOAc afforded the pure compound as a white solid (0.484 g, 6% yield); MW [297. 36] ; C18H19N03 ; Rf 0.23 (50% EtOAc, 50% hexane); 1H NMR (CDC13): 7. [61-] 7.55 (2H, m), 7.50-7. 36 (6H, m), 7.31-7. 25 (2H, m), 5.21 [(1H,] d, 2.3 Hz), 5.09 [(1H,] d, J 7.7 Hz, 2.3 Hz), 4.73 (2H, s, s Hz), 4.37 [(1H,] d, J 7.7 Hz), 4.01 [(1H,] ddd, 12.0 Hz, 2.6 Hz, 1.9 Hz), 3.77 [(1H,] dt, 11.0 Hz, 3.5 Hz), 3.50 [(1H,] dt, 12.0 Hz, 4.0 Hz), 3.16 [(1H,] br. d, 12.0 Hz); LCMS: m/z 298 [M+H] + [&COMMAT; ] Rt 1.24 min (single major peak). |
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