反应详情

To tert-butyl 8-benzyl-10-(1,2-dihydroxyethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (1.5 g, 3.69 mmol) in THF (35 mL) was added NaIO4 (2 g, 9.4 mmol) followed by the addition of H2O (13 mL). The reaction mixture was stirred at room temp for 2.5 hours. The reaction mixture was filtered, then concentrated in vacuo and the residue was partitioned between sat. aq. sodium bicarbonate (50 mL) and ethyl acetate (50 mL). The aqueous layer was extracted further with ethyl acetate (2×50 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated in vacuo. To the intermediate aldehyde (˜1.4 g) was added tBuOH (17 mL) and 2-methylbut-2-ene (10.5 mL, 99.04 mmol) and the reaction mixture was cooled to 0° C. A solution of NaClO2 (1.1 g, 9.65 mmol) and NaH2PO4 (1.33 g, 9.67 mmol) in water (17 mL) was added dropwise over 5 minutes, and the reaction mixture was stirred for 30 minutes at 0° C. The reaction mixture was warmed to room temperature, then extracted with ethyl acetate (4×50 mL) and the combined organics were dried over MgSO4, filtered and concentrated in vacuo to give the crude acid as a yellow oil. The oil was dissolved in toluene (2.5 mL) and methanol (2.5 mL), then diazomethyl(trimethyl)silane (1.85 mL of 2 M in hexanes, 3.69 mmol) was added dropwise until faint yellow color persisted. Acetic acid was added to make solution colorless (2 drops). The reaction mixture was concentrated in vacuo then purified by silica gel column chromatography using 0-70% EtOAc/hexane as eluent to give 9-tert-butyl 2-methyl 4-benzyl-1-oxa-4,9-diazaspiro[5.5]undecane-2,9-dicarboxylate (1 g, 67%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.37-7.20 (m, 5H), 4.43 (dd, J=10.5, 2.1 Hz, 1H), 3.74 (s, 3H), 3.57 (d, J=13.3 Hz, 3H), 3.45-3.29 (m, 2H), 3.14 (t, J=10.9 Hz, 1H), 3.08-3.01 (m, 1H), 2.56 (dd, J=11.3, 0.9 Hz, 1H), 2.30 (dd, J=8.7, 5.7 Hz, 1H), 2.13 (dd, J=19.9, 8.9 Hz, 1H), 1.91 (d, J=11.3 Hz, 1H), 1.69-1.46 (m, 3H), 1.43 (s, 9H). ESI-MS m/z calc. 404.5. Found 405.7 (M+1)+; Retention time: 1.62 (3 min run).

1. filtrationThe reaction mixture was filtered
2. concentrationconcentrated in vacuo
3. customthe residue was partitioned between sat. aq. sodium bicarbonate (50 mL) and ethyl acetate (50 mL)
4. extractionThe aqueous layer was extracted further with ethyl acetate (2×50 mL)
5. dry with materialdried over MgSO4
6. filtrationfiltered
7. concentrationconcentrated in vacuo
8. temperaturethe reaction mixture was cooled to 0° C
9. stirringthe reaction mixture was stirred for 30 minutes at 0° C
10. temperatureThe reaction mixture was warmed to room temperature
11. extractionextracted with ethyl acetate (4×50 mL)
12. dry with materialthe combined organics were dried over MgSO4
13. filtrationfiltered
14. concentrationconcentrated in vacuo
15. customto give the crude acid as a yellow oil
16. concentrationThe reaction mixture was concentrated in vacuo
17. customthen purified by silica gel column chromatography