反应详情

To a stirred solution of (±)-cis-isopropyl (3-hydroxycyclopentanyl)methylphosphinate (6) (1.6 g, 7.8 mmol), DEAD (2.5 cm3, 17.05 mmol) and HN3 (8.2 cm3 of a 1.9 M solution in benzene) in anhydrous THF (70 cm3) under an atmosphere of N2 at 0° C. was added triphenylphosphine (8.15 g, 31.2 mmol) in small portions over a period of 1 h. The reaction mixture was allowed to warm to room temperature and stirring continued for 12 h. The reaction mixture was then heated to 50° C. for 3 h after which time water (2 cm3) was added and heating continued for a further 2 h. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. The residue was partitioned between aqueous HCl (1 M, 30 cm3) and DCM (30 cm3). The organic layer was separated and further extracted with aqueous HCl (2×30 cm3). The combined aqueous fractions were washed with DCM (2×30 cm3) and concentrated in vacuo. The crude amino ester hydrochloride salt was hydrolysed by refluxing in aqueous HCl (6M) for 30 h after which time the reaction mixture was cooled to room temperature and the aqueous HCl removed under reduced pressure. The crude product was purified by ion exchange chromatography (Dowex 50, H+), eluting first with water until the eluate was colourless and pH 7. On further elution with aqueous pyridine (1M), ninhydrin positive fractions were collected and the solvent removed in vacuo giving an off white foam. Recrystallisation from ethanol/acetone followed by drying gave the desired product (7) (0.68 g, 43%): 1H NMR (300 MHz, D2O) δ 1.17 (3H, d, J=12.3 Hz, PCH3), 1.52-2.06 (7H, m, C(1)—H, C(2)—H, C(2)-—H′, C(4)—H, C(4)—H′, C(5)—H and C(5)—H′), 3.73 (1H, m, C(3)—H), 13C NMR (75.46 MHz, D2O) δ 13.16 (PCH3, d, JPC=91.6 Hz), 25.10 (C(5)), 31.31 (C(2)) 30.50 (C(4), d, 3JPC=11.4 Hz), 37.34 (C(1), d, JPC=98.2 Hz), 52.40 (C(3), d, 3JPC=9.7 Hz), 31P NMR (121 MHz, D2O) δ 45.9, MS (CI, CH4) m/z 164 (38%) (MH+), 147 (30), 105 (100), (ESI) 164.0821 (MH+-C6H15NO2P requires 164.0840).

1. additionwas added
2. temperatureheating
3. waitcontinued for a further 2 h
4. temperatureThe reaction mixture was cooled to room temperature
5. customthe solvent removed in vacuo
6. customThe residue was partitioned between aqueous HCl (1 M, 30 cm3) and DCM (30 cm3)
7. customThe organic layer was separated
8. extractionfurther extracted with aqueous HCl (2×30 cm3)
9. washThe combined aqueous fractions were washed with DCM (2×30 cm3)
10. concentrationconcentrated in vacuo
11. temperatureby refluxing in aqueous HCl (6M) for 30 h after which time the reaction mixture
12. temperaturewas cooled to room temperature
13. customthe aqueous HCl removed under reduced pressure
14. customThe crude product was purified by ion exchange chromatography (Dowex 50, H+)
15. washeluting first with water until the eluate
16. washOn further elution with aqueous pyridine (1M), ninhydrin positive fractions
17. customwere collected
18. customthe solvent removed in vacuo
19. customgiving an off white foam
20. customRecrystallisation from ethanol/acetone
21. customby drying