Benzyl Alcohol → methyl (1R,2R,3S,4S)-3-{[(benzyloxy)carbonyl]amino}bicyclo[2.2.1]hept-5-ene-2-carboxylate

Temperature

0 °C

(1S,2S,3R,4R)-3-(Methoxycarbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (5.9 g, 30 mmol) was dissolved in anhydrous tetrahydrofuran (133 mL). The flask was degassed and backfilled with nitrogen and the mixture was cooled to 0° C. Triethylamine (12.64 mL, 90 mmol) was added followed by the dropwise addition of ethyl chloroformate (5.72 mL, 60 mmol) with vigorous stirring. Immediate precipitation was observed. The mixture was stirred at 0° C. for 1 h. Sodium azide (5.86 g, 90 mmol) was dissolved in water (40 mL) and added to the reaction mixture at 0° C. The mixture was stirred at 0° C. for 5 min. The ice bath was removed. The mixture was warmed to 25° C. and continued to stir for 2 h. The mixture was poured into water (300 mL) and the product extracted into ethyl acetate (300 mL). The organic layer was further washed with half-saturated aqueous sodium bicarbonate solution (2×100 mL), saturated aqueous brine solution (100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a light brown oil. The oil was dissolved in anhydrous benzene (66 mL) and refluxed while stirring under nitrogen for 2 h. Upon cooling to 25° C. the solution was concentrated in vacuo to afford a light brown oil. The oil was dissolved in dichloromethane (40 mL) and benzyl alcohol (3.41 mL, 33 mmol) was added followed by triethylamine (8.44 mL, 60 mmol). The mixture was refluxed under nitrogen for 16 h. Upon cooling to 25° C. the solution was concentrated in vacuo to afford a thick oil. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 1st column: 3:1 hexanes/ethyl acetate; 2nd column: 2:4:1 dichloromethane/pentane/diethyl ether) afforded the desired product, methyl (1R,2R,3S,4S)-3-{[(benzyloxy)carbonyl]amino}bicyclo[2.2.1]hept-5-ene-2-carboxylate (6.95 g, 23.09 mmol, 77%), as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ: 1.59 (1H, d, J=9.3 Hz), 1.96 (1H, d, J=9.3 Hz), 2.66 (1H, d, J=7.9 Hz), 2.75 (1H, s), 2.96 (1H, s), 3.59 (3H, s), 4.01 (1H, t, J=8.5 Hz), 5.09 (2H, q, J=10.4 Hz), 5.46 (1H, d, J=9.4 Hz), 6.17-6.22 (2H, m), 7.29-7.36 (5H, m). LC-MS (ESI) calcd for C17H19NO4 301.13. found 258.1 (100%), 302.2 [M+H+] (70%), 603.5 [2M+H+] (20%).

1. customThe flask was degassed
2. customImmediate precipitation
3. additionadded to the reaction mixture at 0° C
4. stirringThe mixture was stirred at 0° C. for 5 min
5. customThe ice bath was removed
6. temperatureThe mixture was warmed to 25° C.
7. stirringto stir for 2 h
8. additionThe mixture was poured into water (300 mL)
9. extractionthe product extracted into ethyl acetate (300 mL)
10. washThe organic layer was further washed with half-saturated aqueous sodium bicarbonate solution (2×100 mL), saturated aqueous brine solution (100 mL)
11. dry with materialdried over magnesium sulfate
12. filtrationfiltered
13. concentrationconcentrated in vacuo
14. customto afford a light brown oil
15. temperaturerefluxed
16. stirringwhile stirring under nitrogen for 2 h
17. temperatureUpon cooling to 25° C. the solution
18. concentrationwas concentrated in vacuo
19. customto afford a light brown oil
20. temperatureThe mixture was refluxed under nitrogen for 16 h
21. temperatureUpon cooling to 25° C. the solution
22. concentrationwas concentrated in vacuo
23. customto afford a thick oil
24. customPurification by flash column chromatography (Merck silica gel 60, 40-63 μm; 1st column: 3:1 hexanes/ethyl acetate; 2nd column: 2:4:1 dichloromethane/pentane/diethyl ether)

ORD record

ord-455fac74ad1f4fc8ae1e237d5d9c23f0

Source dataset

uspto-grants-2013_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08546602B2