反应详情

To a solution of (±)-cis-ethyl (3-hydroxycyclopentanyl)butylphosphinate (10) (1.24 g, 5.29 mmol), DEAD (1.7 cm3) and HN3 (5.6 cm3 of a 1.9 M solution of benzene) in anhydrous THF (50 cm3) under an atmosphere of N2 at 0° C. was added triphenylphosphine (5.52 g, 21.1 mmol) in small portions over a period of 1 hour. The reaction mixture was allowed to warm to room temperature and stirring was continued for 12 hours. The reaction mixture was then heated to 50° C. for 3 hours, then water (2 cm3) was added and heating continued for a further 2 hours. 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 water (3×30 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 (6 M) for 30 hours 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 the pH 7. On further elution with aqueous pyridine (1 M), ninhydrin positive fractions were collected and the solvent was removed in vacuo. The residual traces of pyridine were removed by repeatedly redissolving the compound in water (20 cm3) and re-evaporating (3 times). Recrystallisation from ethanol/acetone followed by drying gave the desired title compound (11) as a pale yellow solid (535 mg, 49%, m.p. (dec.) 145-148° C.): 1H-NMR (300 MHz, D2O) δH 0.78 (3H, t, J=7.2 and 7.2 Hz, PCH2CH2CH2CH3),1.02-2.24 (13H, m, C(1)—H, C(2)—H, C(2)—H′, C(4)—H, C(4)—H′, C(5)—H and C(5)—H′, PCH2CH2CH2CH3, PCH2CH2CH2CH3,PCH2CH2CH2CH3),3.61 (1H, m, C(3)—H); 13C-NMR (75 MHz, D2O) δC 13.45 (s, PCH2CH2CH2CH3), 24.08 and 24.29 (d, 3JPC=15.46 Hz, PCH2CH2CH2CH3), 24.29 and 24.35 (d, 2JPC=5.15 Hz, PCH2CH2CH2CH3), 25.31 (s, C(5)), 27.90 and 29.11 (d, JPC=91.04 Hz, PCH2CH2CH2CH3), 31.38 (s, C(2)), 31.72 and 31.84 (d, 3JPC=9.45 Hz, C(4)), 35.90 and 37.16 (d, JPC=95.05 Hz, C(1)), 52.76 and 52.90 (d, 3JPC=10.59 Hz, C(3)); 31P-NMR (121 MHz, D2O) δP 51.41; MS (ESI) m/z 206.4 (28%) (MH+), 166.9 (100), 102.4 (82), 411.3 (58).

1. temperatureThe reaction mixture was then heated to 50° C. for 3 hours
2. temperatureheating
3. waitcontinued for a further 2 hours
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 water (3×30 cm3)
9. washThe combined aqueous fractions were washed with DCM (2×30 cm3)
10. concentrationconcentrated in vacuo
11. temperatureby refluxing in aqueous HCl (6 M) for 30 hours 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 (1 M), ninhydrin positive fractions
17. customwere collected
18. customthe solvent was removed in vacuo
19. customThe residual traces of pyridine were removed
20. dissolutionby repeatedly redissolving the compound in water (20 cm3)
21. customre-evaporating (3 times)
22. customRecrystallisation from ethanol/acetone
23. customby drying